Arylethynyl derivatives

ABSTRACT

The present invention relates to ethynyl compounds of formula I 
     
       
         
         
             
             
         
       
     
     wherein
 
R1, R2, R2′, R3, R3′, R4, R4′, U, V, W, Y, m, and n are as defined herein and to a pharmaceutically acceptable acid addition salts, to a racemic mixtures, or to its corresponding enantiomers and/or optical isomers and/or stereoisomers thereof. Compounds of formula I are allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5).

PRIORITY TO RELATED APPLICATION(S)

This application is a Divisional of U.S. patent application Ser. No.13/066,044, filed Apr. 5, 2011, now allowed, which claims the benefit ofEuropean Patent Application No. 10159754.0, filed Apr. 13, 2010, whichis hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

In the central nervous system (CNS) the transmission of stimuli takesplace by the interaction of a neurotransmitter, which is sent out by aneuron, with a neuroreceptor.

Glutamate is the major excitatory neurotransmitter in the brain andplays a unique role in a variety of central nervous system (CNS)functions. The glutamate-dependent stimulus receptors are divided intotwo main groups. The first main group, namely the ionotropic receptors,forms ligand-controlled ion channels. The metabotropic glutamatereceptors (mGluR) belong to the second main group and, furthermore,belong to the family of G-protein coupled receptors.

At present, eight different members of these mGluR are known and ofthese some even have sub-types. According to their sequence homology,signal transduction mechanisms and agonist selectivity, these eightreceptors can be sub-divided into three sub-groups:

mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to groupII and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the first groupcan be used for the treatment or prevention of acute and/or chronicneurological disorders such as psychosis, epilepsy, schizophrenia,Alzheimer's disease, cognitive disorders and memory deficits, as well aschronic and acute pain.

Other treatable indications in this connection are restricted brainfunction caused by bypass operations or transplants, poor blood supplyto the brain, spinal cord injuries, head injuries, hypoxia caused bypregnancy, cardiac arrest and hypoglycaemia. Further treatableindications are ischemia, Huntington's chorea, amyotrophic lateralsclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy,idiopathic parkinsonism or parkinsonism caused by medicaments as well asconditions which lead to glutamate-deficiency functions, such as e.g.muscle spasms, convulsions, migraine, urinary incontinence, nicotineaddiction, opiate addiction, anxiety, vomiting, dyskinesia anddepressions.

Disorders mediated full or in part by mGluR5 are for example acute,traumatic and chronic degenerative processes of the nervous system, suchas Alzheimer's disease, senile dementia, Parkinson's disease,Huntington's chorea, amyotrophic lateral sclerosis and multiplesclerosis, psychiatric diseases such as schizophrenia and anxiety,depression, pain and drug dependency (Expert Opin. Ther. Patents (2002),12, (12)).

A new avenue for developing selective modulators is to identifycompounds which act through allosteric mechanism, modulating thereceptor by binding to a site different from the highly conservedorthosteric binding site. Allosteric modulators of mGluR5 have emergedrecently as novel pharmaceutical entities offering this attractivealternative. Allosteric modulators have been described, for example inWO2008/151184, WO2006/048771, WO2006/129199 and WO2005/044797 and inMolecular Pharmacology, 40, 333-336, 1991; The Journal of Pharmacologyand Experimental Therapeutics, Vol 313, No. 1, 199-206, 2005;

In recent years there have been significant advantages in understandingthe pathophysiology of several disorders of brain development,suggesting that protein synthesis at synapses is triggered by activationof group I metabotropic glutamate receptors. Such disorders includefragile X syndrome, autism, idiopatic autism, tuberous sclerosis complexdisorder, neurofibromatosis type 1 or Rett syndrome (Annu. Rev. Med.,2011, 62, 31.1-31.19 and Neuroscience 156, 2008, 203-215).

Described in the prior art are positive allosteric modulators. They arecompounds that do not directly activate receptors by themselves, butmarkedly potentiate agonist-stimulated responses, increase potency andmaximum of efficacy. The binding of these compounds increases theaffinity of a glutamate-site agonist at its extracellular N-terminalbinding site. Allosteric modulation is thus an attractive mechanism forenhancing appropriate physiological receptor activation. There is ascarcity of selective allosteric modulators for the mGluR5 receptor.Conventional mGluR5 receptor modulators typically lack satisfactoryaqueous solubility and exhibit poor oral bioavailability.

Therefore, there remains a need for compounds that overcome thesedeficiencies and that effectively provide selective allostericmodulators for the mGluR5 receptor.

SUMMARY OF THE INVENTION

The present invention provides ethynyl compounds of formula I

wherein

-   U is ═N— or ═C(R⁵)—;-   V is —CH═ or —N═;-   W is ═CH— or ═N—;    -   with the proviso that only one of U, V or W is nitrogen,-   R⁵ is hydrogen, methyl or halogen;-   Y is —N(R⁶)—, —O—, —C(R^(7′))(R⁷)—, —CH₂O— or —CH₂S(O)₂—;    -   wherein R⁶ is hydrogen or lower alkyl and R⁷ and R^(7′) are each        independently hydrogen, hydroxy, lower alkyl or lower alkoxy;-   R¹ is phenyl or heteroaryl, each of which is optionally substituted    by one or two substituents, selected from halogen, lower alkyl and    lower alkoxy;-   R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy,    lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together    with the carbon atom to which they are attached form a    C₃-C₆-cycloalkyl group or a ring containing —CH₂OCH₂—;-   m is 0, 1 or 2;    -   when m is 1,-   R³ and R^(3′) are each independently hydrogen, lower alkyl, or    CH₂-lower alkoxy or together with the carbon atom to which they are    attached form a C₃-C₆-cycloalkyl group;    -   or R³ and R² together with the carbon atom to which they are        attached form a C₃₋₆-cycloalkyl group or a ring containing        —(CH₂)₂OCH₂—;-   n is 0 or 1; and    -   when n is 1,-   R⁴ and R^(4′) are each independently hydrogen, lower alkyl, or    CH₂-lower alkoxy or together with the carbon atom to which they are    attached form a C₃-C₆-cycloalkyl; or    -   R⁴ and R² together with the carbon atom to which they are        attached form a C₃₋₆-cycloalkyl group;        or when n is 0 and Y is —N(R⁶)—, then R⁶ and R² together with        the carbon atom and the nitrogen atom to which they are attached        form a C₃₋₆-cycloalkyl group;        or when n and m are 0, then R² and R⁷ together with the carbon        atoms to which they are attached form a C₃₋₆-cycloalkyl group;        or a pharmaceutically acceptable acid addition salt, a racemic        mixture, an enantiomer, an isomer, and/or a stereoisomer        thereof.

The present invention provides compounds of formula I per se, theirpharmaceutically acceptable salts, and mixtures of enantiomers ordiastereomers or their enantiomerically or diastereomerically pureforms. The invention also provides pharmaceutical compositionscontaining a theroapeutically effective amount of such compounds andprocess for the production of such compounds and compositions.

Compounds of formula I are allosteric modulators of the metabotropicglutamate receptor subtype 5 (mGluR5). They can be used in the treatmentor prevention of disorders relating to allosteric modulators for themGluR5 receptor. For example, the compounds can be used for thetreatment or prevention of disorders, relating to allosteric modulatorsfor the mGluR5 receptor, such as schizophrenia, cognition, fragile Xsyndrome or autism, and to pharmaceutical compositions containing thecompounds of formula I. The most preferred indications are schizophreniaand cognition.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of the general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination.

As used herein, the term “lower alkyl” denotes a saturated, i.e.aliphatic hydrocarbon group including a straight or branched carbonchain with 1-4 carbon atoms. Examples for “alkyl” are methyl, ethyl,n-propyl, and isopropyl.

The term “lower alkoxy” denotes a group —O—R′ wherein R′ is lower alkylas defined above.

The term “halogen” denotes the chlorine, fluorine, bromine, or iodine.

The term “ethynyl” denotes the group —C≡C—.

The term “cycloalkyl” denotes a saturated carbon ring, containing from 3to 6 carbon ring atoms, for example cyclopropyl, cyclobutyl, cyclopentylor cyclohexyl.

The term “heteroaryl” denotes a 5 or 6-membered aromatic ring,containing at least one N, O or S-heteroatom, for example pyridinyl,pyrimidinyl, pyrazolyl, pyridazinyl, imidazolyl, triazolyl, thienyl orpyrazinyl.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., denotes pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The term “pharmaceutically acceptable salt” or “pharmaceuticallyacceptable acid addition salt” embraces salts with inorganic and organicacids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoricacid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid,succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonicacid and the like.

“Therapeutically effective amount” denotes an amount that is effectiveto prevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

One embodiment of the invention provides compounds of formula I-1

wherein

-   U is ═N— or ═C(R⁵)—;-   V is —CH═ or —N═;-   W is ═CH— or ═N—;    -   with the proviso that only one of U, V or W is nitrogen.-   R⁵ is hydrogen, methyl or halogen;-   R¹ is phenyl or heteroaryl, each of which is optionally substituted    by one or two substituents, selected from halogen, lower alkyl and    lower alkoxy;-   R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy,    lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together    with the carbon atom to which they are attached form a    C₃-C₆-cycloalkyl group or a ring containing    -   —CH₂OCH₂—; and-   R³ and R^(3′) are each independently hydrogen, lower alkyl, or    CH₂-lower alkoxy or together with the carbon atom to which they are    attached form a C₃-C₆-cycloalkyl group;    -   or R³ and R² together with the carbon atom to which they are        attached form a C₃₋₆-cycloalkyl group or a ring containing        —(CH₂)₂OCH₂—;        or a pharmaceutically acceptable acid addition salt, a racemic        mixture, an enantiomer, an optical isomer, and/or stereoisomer        thereof.

Examples of compounds of formula I-A1 are the following:

-   3-(3-fluoro-5-phenylethynyl-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one;-   (5RS)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;-   (5R or    5S)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;-   (5S or    5R)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;-   5,5-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;-   3-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one;-   5,5-dimethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-oxazolidin-2-one;-   (5RS)-5-tert-butyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;-   6-(5-phenylethynyl-pyridin-2-yl)-4-oxa-6-aza-spiro[2.4]heptan-5-one;-   7-(5-phenylethynyl-pyridin-2-yl)-5-oxa-7-aza-spiro[3.4]octan-6-one;-   3-(5-phenylethynyl-pyridin-2-yl)-1-oxa-3-aza-spiro[4.4]nonan-2-one;-   3-(5-phenylethynyl-pyridin-2-yl)-1-oxa-3-aza-spiro[4.5]decan-2-one;-   (5RS)-5-tert-butyl-5-methyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;-   (3aRS,6aSR)-3-(5-phenylethynyl-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one;-   (3aRS,6aSR)-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one;-   (3aRS,6aSR)-3-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-hexahydro-cyclopentaoxazol-2-one;-   (RS)-4,5,5-trimethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;-   4,4,5,5-tetramethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;-   3-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one;-   5,5-dimethyl-3-(5-pyrimidin-5-ylethynyl-pyridin-2-yl)-oxazolidin-2-one;-   5,5-dimethyl-3-[5-(1-methyl-1H-pyrazol-4-ylethynyl)-pyridin-2-yl]-oxazolidin-2-one;-   3-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one;-   3-[5-(3,4-difluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one;-   3-[5-(2,5-difluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one;-   3-[5-(6-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one;-   6-(5-pyridin-3-ylethynyl-pyridin-2-yl)-4-oxa-6-aza-spiro[2.4]heptan-5-one;-   (6SR,7RS)-3-(5-phenylethynyl-pyridin-2-yl)-hexahydro-benzooxazol-2-one;-   (3aSR,7aRS)-(3aRS,7RS)-1-(5-phenylethynyl-pyridin-2-yl)-hexahydro-pyrano[4,3-d]oxazol-2-one;    and-   5,5-dimethyl-3-(6-(phenylethynyl)pyridazin-3-yl)oxazolidin-2-one.

A further embodiment of the invention provides compounds of formula I-B1

wherein

-   U is ═N— or ═C(R⁵)—;-   V is —CH═ or —N═;-   W is ═CH— or ═N—;    -   with the proviso that only one of U, V or W is nitrogen.-   R⁵ is hydrogen, methyl or halogen;-   R¹ is phenyl or heteroaryl, each of which is optionally substituted    by one or two substituents, selected from halogen, lower alkyl and    lower alkoxy;-   R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy,    lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together    with the carbon atom to which they are attached form a    C₃-C₆-cycloalkyl group or a ring containing    -   —CH₂OCH₂—;-   R³ and R^(3′) are each independently hydrogen, lower alkyl, or    CH₂-lower alkoxy or together with the carbon atom to which they are    attached form a C₃-C₆-cycloalkyl group;    -   or R³ and R² together with the carbon atom to which they are        attached form a C₃₋₆-cycloalkyl group or a ring containing        —(CH₂)₂OCH₂—; and-   R⁷ and R^(7′) are each independently hydrogen, hydroxy, lower alkyl    or lower alkoxy;    or a pharmaceutically acceptable acid addition salt, a racemic    mixture, an enantiomer, an optical isomer, and/or stereoisomer    thereof.

Specific examples of compounds of formula I-B 1 are the following:

-   4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one;-   (3RS)-3-hydroxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one;-   1-(3-fluoro-5-phenylethynyl-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one;-   1-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one;-   4,4-dimethyl-1-(5-pyridin-3-ylethynyl-pyridin-2-yl)-pyrrolidin-2-one;-   1-[5-(5-chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one;-   1-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one;-   4,4-dimethyl-1-(3-methyl-5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one;-   2-(5-phenylethynyl-pyridin-2-yl)-2-aza-spiro[4.4]nonan-3-one;-   (RS)-3-methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one;-   (5R or    5S)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;-   (5S or    5R)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;-   (RS)-1-[5-(5-chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one;-   (RS)-3-methoxy-4,4-dimethyl-1-(5-m-tolylethynyl-pyridin-2-yl)-pyrrolidin-2-one;-   (RS)-1-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one;-   (RS)-1-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one;-   6-(5-phenylethynyl-pyridin-2-yl)-2-oxa-6-aza-spiro[3.4]octan-7-one;-   4,4-dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one;-   5′-(3-fluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one;-   5′-(3-chloro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one;-   5′-(5-chloro-pyridin-3-ylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one;-   5′-(4-fluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one;-   5′-(2,5-difluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one;-   4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one;-   2-(5-phenylethynyl-pyrimidin-2-yl)-2-aza-spiro[4.4]nonan-3-one;-   1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one;-   1-[5-(3-chloro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one;-   1-[5-(4-fluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one;-   1-[5-(2,5-difluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one;-   (RS)-3-methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one;-   (5R or    5S)-5-methoxymethyl-3-(5-phenylethynyl-pyrimidin-2-yl)-oxazolidin-2-one;-   (5S or    5R)-5-methoxymethyl-3-(5-phenylethynyl-pyrimidin-2-yl)-oxazolidin-2-one;-   (RS)-1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one;-   (R or    S)-1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one;-   (S or    R)-1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one;-   (R or    S)-1-[5-(2,5-difluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one;-   4,4-dimethyl-1-(6-(phenylethynyl)pyridazin-3-yl)pyrrolidin-2-one;    and-   4,4-dimethyl-1-(5-(pyridin-3-ylethynyl)pyrazin-2-yl)pyrrolidin-2-one.

A further embodiment of the invention provides compounds of formula I-C1

wherein

-   U is ═N— or ═C(R⁵)—;-   V is —CH═ or —N═;-   W is ═CH— or ═N—;    -   with the proviso that only one of U, V or W is nitrogen.-   R⁵ is hydrogen, methyl or halogen;-   R⁶ is hydrogen or lower alkyl;-   R¹ is phenyl or heteroaryl, each of which is optionally substituted    by one or two substituents, selected from halogen, lower alkyl and    lower alkoxy;-   R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy,    lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together    with the carbon atom to which they are attached form a    C₃-C₆-cycloalkyl group or a ring containing    -   —CH₂OCH₂—; and-   R³ and R^(3′) are each independently hydrogen, lower alkyl, or    CH₂-lower alkoxy or together with the carbon atom to which they are    attached form a C₃-C₆-cycloalkyl group;    -   or R³ and R² together with the carbon atom to which they are        attached form a C₃₋₆-cycloalkyl group or a ring containing        —(CH₂)₂OCH₂—;-   or R⁶ and R² together with the carbon atom and the nitrogen atom to    which they are attached form a C₃₋₆-cycloalkyl;    or a pharmaceutically acceptable acid addition salt, a racemic    mixture, an enantiomer, an optical isomer and/or stereoisomer    thereof.

Examples of compounds of formula I-C1 are the following:

-   4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one;-   3,4,4-trimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one;-   3-ethyl-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one;-   3-isopropyl-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one;-   1-methyl-3-(5-phenylethynyl-pyridin-2-yl)-1,3-diaza-spiro[4.4]nonan-2-one;-   (RS)-4-cyclopentyl-3-methyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one;-   3,4,4-trimethyl-1-(5-pyridin-3-ylethynyl-pyridin-2-yl)-imidazolidin-2-one;-   1-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;-   3,4,4-trimethyl-1-[5-(1-methyl-1H-pyrazol-4-ylethynyl)-pyridin-2-yl]-imidazolidin-2-one;-   1-[5-(5-chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;-   3,4,4-trimethyl-1-(5-pyridazin-4-ylethynyl-pyridin-2-yl)-imidazolidin-2-one;-   1-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;-   1-[5-(3-chloro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;-   3,4,4-trimethyl-1-(5-pyrimidin-5-ylethynyl-pyridin-2-yl)-imidazolidin-2-one;-   3,4,4-trimethyl-1-(5-m-tolylethynyl-pyridin-2-yl)-imidazolidin-2-one;-   1-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;-   (RS)-2-(5-phenylethynyl-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one;-   (RS)-2-(5-pyridin-3-ylethynyl-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one;-   (RS)-2-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-hexahydro-imidazo[1,5-a]pyridin-3-one;-   (RS)-4-cyclopropyl-3-methyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one;-   (3aSR,7aRS)-(3aRS,7RS)-1-methyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one;-   (3aSR,7aRS)-(3aRS,7RS)-1-methyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one;-   (3aSR,7aRS)-(3aRS,7RS)-1-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-3-methyl-octahydro-benzoimidazol-2-one;-   4-methyl-6-(5-phenylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one;-   (3aSR,7aRS)-(3aRS,7RS)-1-ethyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one;-   (3aSR,7aRS)-(3aRS,7RS)-1-ethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one;-   (3aSR,7aRS)-(3aRS,7RS)-1-isopropyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one;-   (3aRS,6aSR)-1-methyl-3-(5-(phenylethynyl)pyridin-2-yl)hexahydrocyclopenta[d]imidazol-2(1H)-one;-   (RS)-4-tert-butyl-3-methyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one;-   1-[5-(3-fluoro-phenylethynyl)-3-methyl-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;-   (3aSR,6aRS)-1-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-3-methyl-hexahydro-cyclopenta-imidazol-2-one;-   1-[3-fluoro-5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;-   1-[3-fluoro-5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;-   6-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-4-methyl-4,6-diaza-spiro[2.4]heptan-5-one;-   6-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-4-methyl-4,6-diaza-spiro[2.4]heptan-5-one;-   3,4,4-trimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-imidazolidin-2-one;-   1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;-   1-[5-(2,5-difluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;-   1-[5-(4-fluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;-   1-[5-(3,4-di-fluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;-   3-isopropyl-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-imidazolidin-2-one;-   1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-isopropyl-4,4-dimethyl-imidazolidin-2-one;-   1-[5-(4-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-isopropyl-4,4-dimethyl-imidazolidin-2-one;-   1-[5-(4-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-ethyl-4,4-dimethyl-imidazolidin-2-one;-   1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-ethyl-4,4-dimethyl-imidazolidin-2-one;-   4-methyl-6-(5-phenylethynyl-pyrimidin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one;-   3,4,4-trimethyl-1-(6-(m-tolylethynyl)pyridazin-3-yl)imidazolidin-2-one;-   1-(6-((3-chlorophenyl)ethynyl)pyridazin-3-yl)-3,4,4-trimethylimidazolidin-2-one;-   3,4,4-trimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)imidazolidin-2-one;-   3,4,4-trimethyl-1-(5-(pyridin-3-ylethynyl)pyrazin-2-yl)imidazolidin-2-one;-   1-(5-((3-fluorophenyl)ethynyl)pyrazin-2-yl)-3,4,4-trimethylimidazolidin-2-one;-   1-(5-((4-fluorophenyl)ethynyl)pyrazin-2-yl)-3,4,4-trimethylimidazolidin-2-one;-   (3aRS,6aSR)-1-methyl-3-(6-phenylethynyl-pyridazin-3-yl)-hexahydro-cyclopentaimidazol-2-one;    and-   (3aSR,6aRS)-1-[6-(3-fluoro-phenylethynyl)-pyridazin-3-yl]-3-methyl-hexahydro-cyclopentaimidazol-2-one.

A further embodiment of the invention provides compounds of formula I-D1

wherein

-   U is ═N— or ═C(R⁵)—;-   V is —CH═ or —N═;-   W is ═CH— or ═N—;    -   with the proviso that only one of U, V or W is nitrogen.-   R⁵ is hydrogen, methyl or halogen;-   R¹ is phenyl or heteroaryl, each of which is optionally substituted    by one or two substituents, selected from halogen, lower alkyl and    lower alkoxy;-   R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy,    lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together    with the carbon atom to which they are attached form a    C₃-C₆-cycloalkyl group or a ring containing    -   —CH₂OCH₂—;-   R³ and R^(3′) are each independently hydrogen, lower alkyl, or    CH₂-lower alkoxy or together with the carbon atom to which they are    attached form a C₃-C₆-cycloalkyl group;    -   or R³ and R² together with the carbon atom to which they are        attached form a C₃₋₆-cycloalkyl group or a ring containing        —(CH₂)₂OCH₂—; and-   R⁴ and R^(4′) are each independently hydrogen, lower alkyl, or    CH₂-lower alkoxy or together with the carbon atom to which they are    attached from a C₃-C₆-cycloalkyl;-   R⁴ and R² together with the carbon atom to which they are attached    form a C₃₋₆-cycloalkyl;    or a pharmaceutically acceptable acid addition salt, a racemic    mixture, an enantiomer, an optical isomer and/or stereoisomer    thereof.

Examples of compounds of formula I-D1 are the following:

-   5,5-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one;-   6,6-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one;-   6,6-dimethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one;-   3-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one;-   3-[5-(5-chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one;-   3-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one;-   3-[5-(3-chloro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one;-   6,6-dimethyl-3-(5-m-tolylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one;-   3-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one;-   3-[5-(3,4-difluoro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one;-   3-[5-(2,5-difluoro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one;-   7,7-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazepan-2-one;-   (RS)-5-hydroxy-6,6-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one;-   (4aRS,7aSR)-3-(5-phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one;-   (4aRS,7aRS)-3-(5-phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one;-   (RS)-5,6,6-trimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one;-   (RS)-6-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one;-   (RS)-5-methoxy-6,6-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one;-   (RS)-5,6,6-trimethyl-3-(5-phenylethynyl-pyrimidin-2-yl)-[1,3]oxazinan-2-one;-   (RS)-3-[5-(2,5-difluoro-phenylethynyl)-pyrimidin-2-yl]-5,6,6-trimethyl-[1,3]oxazinan-2-one;-   (RS)-3-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-5,6,6-trimethyl-[1,3]oxazinan-2-one;-   (RS)-3-[5-(4-fluoro-phenylethynyl)-pyrimidin-2-yl]-5,6,6-trimethyl-[1,3]oxazinan-2-one;-   6,6-dimethyl-3-(6-(phenylethynyl)pyridazin-3-yl)-1,3-oxazinan-2-one;-   6,6-dimethyl-3-(5-(phenylethynyl)pyrazin-2-yl)-1,3-oxazinan-2-one;    and-   (RS)-3-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-5-methoxy-6,6-dimethyl-[1,3]oxazinan-2-one.

A further embodiment of the invention provides compounds of formula I-E1

wherein

-   U is ═N— or ═C(R⁵)—;-   V is —CH═ or —N═;-   W is ═CH— or ═N—;    -   with the proviso that only one of U, V or W is nitrogen.-   R⁵ is hydrogen, methyl or halogen;-   R⁷ and R^(7′) are each independently hydrogen, hydroxy, lower alkyl    or lower alkoxy;-   R¹ is phenyl or heteroaryl, each of which is optionally substituted    by one or two substituents, selected from halogen, lower alkyl and    lower alkoxy;-   R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy,    lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together    with the carbon atom to which they are attached form a    C₃-C₆-cycloalkyl group or a ring containing    -   —CH₂OCH₂—;-   R³ and R^(3′) are each independently hydrogen, lower alkyl, or    CH₂-lower alkoxy or together with the carbon atom to which they are    attached form a C₃-C₆-cycloalkyl group;    -   or R³ and R² together with the carbon atom to which they are        attached form a C₃₋₆-cycloalkyl group or a ring containing        —(CH₂)₂OCH₂—; and-   R⁴ and R^(4′) are each independently hydrogen, lower alkyl, or    CH₂-lower alkoxy or together with the carbon atom to which they are    attached form a C₃-C₆-cycloalkyl group;-   R⁴ and R² together with the carbon atom to which they are attached    form a C₃₋₆-cycloalkyl group;    or a pharmaceutically acceptable acid addition salt, a racemic    mixture, an enantiomer, an optical isomer and/or stereoisomer    thereof.

Specific examples of compounds of formula I-E1 are the following:

-   5,5-dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one;-   5′-(3-fluoro-phenylethynyl)-5,5-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one;-   5,5-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-piperidin-2-one;-   4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-piperidin-2-one;-   1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-piperidin-2-one;-   1-[5-(2,5-difluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-piperidin-2-one;-   4,4-dimethyl-1-(6-(phenylethynyl)pyridazin-3-yl)piperidin-2-one;-   1-(5-((3-fluorophenyl)ethynyl)pyrazin-2-yl)-4,4-dimethylpiperidin-2-one;-   4,4-dimethyl-1-(5-(pyridin-3-ylethynyl)pyrazin-2-yl)piperidin-2-one;    and-   4,4-dimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)piperidin-2-one.

A further embodiment of the invention provides compounds of formula I-F1

wherein

-   U is ═N— or ═C(R⁵)—;-   V is —CH═ or —N═;-   W is ═CH— or ═N—;    -   with the proviso that only one of U, V or W is nitrogen.-   R⁵ is hydrogen, methyl or halogen;-   R⁶ is hydrogen or lower alkyl;-   R¹ is phenyl or heteroaryl, each of which is optionally substituted    by one or two substituents, selected from halogen, lower alkyl and    lower alkoxy;-   R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy,    lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together    with the carbon atom to which they are attached form a    C₃-C₆-cycloalkyl group or a ring containing    -   —CH₂OCH₂—;-   R³ and R^(3′) are each independently hydrogen, lower alkyl, or    CH₂-lower alkoxy or together with the carbon atom to which they are    attached form a C₃-C₆-cycloalkyl group;    -   or R³ and R² together with the carbon atom to which they are        attached form a C₃₋₆-cycloalkyl group or a ring containing        —(CH₂)₂OCH₂—; and-   R⁴ and R^(4′) are each independently hydrogen, lower alkyl, or    CH₂-lower alkoxy or together with the carbon atom to which they are    attached form a C₃-C₆-cycloalkyl group; or-   R⁴ and R² together with the carbon atom to which they are attached    form a C₃₋₆-cycloalkyl;    or a pharmaceutically acceptable acid addition salt, a racemic    mixture, an enantiomer, an optical isomer and/or stereoisomer    thereof.

Examples of compounds of formula I-F1 are the following:

-   5,5-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one;-   1,5,5-trimethyl-3-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one;-   3,4,4-trimethyl-1-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one;-   1-[5-(2,5-difluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-tetrahydro-pyrimidin-2-one;-   1-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-tetrahydro-pyrimidin-2-one;-   3,4,4-trimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one;-   5′-(3-fluoro-phenylethynyl)-3,4,4-trimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one;-   5′-(2,5-difluoro-phenylethynyl)-3,4,4-trimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one;-   4,4-dimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)tetrahydropyrimidin-2(1H)-one;-   3,4,4-trimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)tetrahydropyrimidin-2(1H)-one;-   1-(5-((3-fluorophenyl)ethynyl)pyrazin-2-yl)-4,4-dimethyltetrahydropyrimidin-2(1H)-one;    and-   1-(5-((3-fluorophenyl)ethynyl)pyrazin-2-yl)-3,4,4-trimethyltetrahydropyrimidin-2(1H)-one.

A further embodiment of the invention provides compounds of formula I-G1

wherein

-   U is ═N— or ═C(R⁵)—;-   V is —CH═ or —N═;-   W is ═CH— or ═N—;    -   with the proviso that only one of U, V or W is nitrogen.-   R⁵ is hydrogen, methyl or halogen;-   Y is —N(R⁶)—, —O—, —C(R^(7′))(R⁷)—, —CH₂O— or —CH₂S(O)₂—;    -   wherein R⁶ is hydrogen or lower alkyl and R⁷ and R^(7′) are each        independently hydrogen, hydroxy, lower alkyl and lower alkoxy;-   R¹ is phenyl or heteroaryl, each of which is optionally substituted    by one or two substituents, selected from halogen, lower alkyl and    lower alkoxy; and-   R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy,    lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together    with the carbon atom to which they are attached form a    C₃-C₆-cycloalkyl group or a ring containing    -   —CH₂OCH₂—;-   or R⁶ and R² together with the carbon atom and the nitrogen atom to    which they are attached form a C₃₋₆-cycloalkyl group;-   or R² and R⁷ together with the carbon atoms to which they are    attached form a C₃₋₆-cycloalkylgroup;    or a pharmaceutically acceptable acid addition salt, a racemic    mixture, an enantiomer, an optical isomer and/or stereoisomer    thereof.

Examples of compounds of formula I-G1 are the following:

-   (1 RS,5    SR)-6-(5-phenylethynyl-pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7-one;-   3,3-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-azetidin-2-one; and-   (1RS,5SR)-6-(5-pyridin-3-ylethynyl-pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7-one.

The invention further provides compounds of formula I, wherein Y is—CH₂O—, for example

-   (RS)-6-methyl-4-(5-phenylethynyl-pyridin-2-yl)-morpholin-3-one and-   6,6-dimethyl-4-(5-phenylethynyl-pyridin-2-yl)-morpholin-3-one.

The invention further provides compounds of formula I, wherein Y is—CH₂S(O)₂—, for example1,1-dioxo-4-(5-phenylethynyl-pyridin-2-yl)-thiomorpholin-3-one.

The invention also provides compounds of formula I, wherein m is 2, forexample7,7-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazepan-2-one.

The invention provides ethynyl compounds of formula Ia

wherein

-   X is N or C—R⁵,    -   wherein R⁵ is hydrogen or halogen;-   Y is N—R⁶, O or CHR⁷,    -   wherein R⁶ is hydrogen or lower alkyl and R⁷ is hydrogen,        hydroxy, lower alkyl or lower alkoxy;-   R¹ is phenyl or heteroaryl, each of which is optionally substituted    by halogen, lower alkyl or lower alkoxy;-   R² and R^(2′) are each independently hydrogen, lower alkyl, or    CH₂-lower alkoxy or together with the carbon atom to which they are    attached form a C₃-C₆-cycloalkyl group;-   m is 0 or 1; when m is 1,-   R³ and R^(3′) are each independently hydrogen, lower alkyl, or    CH₂-lower alkoxy or together with the carbon atom to which they are    attached form a C₃-C₆-cycloalkyl group; and-   n is 0 or 1; when n is 1,-   R⁴ and R^(4′) are each independently hydrogen, lower alkyl, or    CH₂-lower alkoxy or together with the carbon atom to which they are    attached form a C₃-C₆-cycloalkyl group;-   or when m is 1 and n is 0, R³ and R² together with the carbon atoms    to which they are attached form a C₃₋₆-cycloalkyl group;-   or when m is 0 and m is 1, R⁴ and R² together with the carbon atoms    to which they are attached form a C₃₋₆-cycloalkyl group;    or a pharmaceutically acceptable acid addition salt, racemic    mixture, an enantiomer, an optical isomer, and/or stereoisomer    thereof.

The preparation of compounds of formula I of the present invention canbe carried out in sequential or convergent synthetic routes. Synthesesof the compounds of the invention are shown in the following schemes 1to 3. The skills required for carrying out the reaction and purificationof the resulting products are known to those skilled in the art. Thesubstituents and indices used in the following description of theprocesses have the significance given herein before.

The compounds of formula I can be manufactured by the methods givenbelow, by the methods given in the examples or by analogous methods.Appropriate reaction conditions for the individual reaction steps areknown to a person skilled in the art. The reaction sequence is notlimited to the one displayed in the schemes, however, depending on thestarting materials and their respective reactivity the sequence ofreaction steps can be freely altered. Starting materials are eithercommercially available or can be prepared by methods analogous to themethods given below, by methods described in references cited in thedescription or in the examples, or by methods known in the art.

The present compounds of formula I and their pharmaceutically acceptablesalts can be prepared by methods, known in the art, for example by theprocess variant described below, which process comprises reacting acompound of formula

wherein X is a suitable leaving group which can be substituted by anacetylene moiety such as, for example a bromine or iodine atom, atrialkylstannyl group, a boronic acid or boronic ester group with asuitable aryl-acetylene of formula

to obtain a compound of formula

wherein the substituents are described above, orif desired, converting the compounds obtained into pharmaceuticallyacceptable acid addition salts.

The preparation of compounds of formula I is further described in moredetail in schemes 1 to 6 and in examples 1-174.

A ethynyl-pyridine, ethynyl-pyrimidine, ethynyl-pyrazine orethynyl-pyridazine compound of formula I-A can be obtained bysubstitution of an appropriate 5-iodo-2-fluoro-pyridine,5-iodo-2-fluoro-pyrimidine, 2-chloro-5-iodopyridazine or2-bromo-5-iodopyrazine 1 or the like and an appropriate aminoalcohol 2with a base such as pyridine, triethylamine, or cesium carbonate in asolvent such as NMP, pyridine, or dioxane to yield the corresponding5-iodo-2-aminoalkoxy-adducts of formula 3, which are treated withphosgene or a phosgene equivalent such as triphosgene in presence ofbase such as pyridine in a solvent like dichloromethane to give thecorresponding cyclized urethane- or urea-derivatives 4. Sonogashiracoupling of the iodo-heteroaryl derivatives 4 with an appropriatelysubstituted arylacetylene 5 yield the desired ethynyl compounds ofgeneral formula I-A or I-D (scheme 1).

An ethynyl-pyridine, ethynyl-pyrimidine, ethynyl-pyrazine orethynyl-pyridazine compound of formula I-B can be obtained by reactingan appropriate 5-iodo-2-amino-pyridine- or 5-iodo-2-amino-pyrimidine-,5-iodo-2-amino-pyrazine, or 5-iodo-2-amino-pyridazine derivative 6 orthe like with an appropriately substituted anhydride 7 in a solvent suchas DMF to yield the corresponding imide derivative 8, which is reducedwith a reducing agent such as sodium borohydride in a solvent such asTHF and/or MeOH to give the corresponding alcohol derivative 9. Reactingcompound 9 with trifluoroacetic anhydride in a solvent likedichloromethane followed by reduction with triethylsilane in a solventlike TFA yields the desired amide 10. Sonogashira coupling of the amide10 with an appropriately substituted aryl-acetylene 5 yields the desiredethynyl-compounds of formula I-B or I-E (scheme 2).

An ethynyl-pyridine, ethynyl-pyrimidine, ethynyl-pyrazine orethynyl-pyridazine compound of formula I-C can be obtained bysubstitution of an appropriate 5-iodo-2-fluoro-pyridine,5-iodo-2-fluoro-pyrimidine, 2-chloro-5-iodopyridazine or2-bromo-5-iodopyrazine 1 or the like (1) wherein Y is a suitable leavinggroup which can be displaced via nucleophillic substitution by an aminesuch as a fluorine, chlorine, or bromine atom or an alkysulfonyl groupwith an appropriate diaminoalkyl derivative 11 in presence of a basesuch as pyridine or cesium carbonate in a solvent like NMP, pyridine, ordioxane to yield the corresponding N-heteroaryl derivative 12, which iscyclized with phosgene or a phosgene equivalent in presence of a basesuch as pyridine or triethylamine in a solvent like dichloromethane orTHF to give the corresponding urea derivative 13 which is then coupledwith an appropriately substituted aryl-acetylene 5 to yield the desiredethynyl-compound of formula I-C or I-F (scheme 3).

An ethynyl-pyridine or ethynyl-pyrimidine compound of formula I can beobtained for example by Sonogashira coupling of a2-bromo-5-iodo-pyridine, 2-bromo-5-iodo-pyrimidine,2-bromo-5-iodopyridazine or 2-bromo-5-iodopyrazine 1 or the like withethynyltrimethylsilane 15 to yield the2-bromo-5-trimethylsilanylethynyl-substituted heteroaryl derivatives 16.Substitution of 16 with an appropriate lactam, cyclic carbamate orcyclic urea derivative 17 in presence of a base such as cesiumcarbonate, or using xantphos and Pd₂(dba)₃ in a solvent like tolueneyields the corresponding 5-trimethylsilanylethynyl derivatives 18.Sonogashira coupling with in-situ desilylation of 18 in presence offluoride and an appropriately substituted aryl-halogenide 19 yields thedesired arylethynyl-compounds of formula I (scheme 4).

An arylethynyl compound of formula I can be obtained by Sonogashiracoupling of a 5-bromo- or 5-iodo-heteroaryl derivative 4, 10 or 13(where Y═Br, I) with ethynyltrimethylsilane 15 to yield thecorresponding 5-trimethylsilanylethynyl-derivatives 18. Sonogashiracoupling with in-situ desilylation of 18 and an appropriatelysubstituted aryl-halogenide 19 yields the desired ethynyl-pyridine orethynyl-pyrimidine compounds of formula I (scheme 5).

Generally speaking, the sequence of steps used to synthesize thecompounds of formula I can also be modified in certain cases, forexample by first running the Sonogashira coupling with an appropriatelysubstituted aryl- or heteroaryl-ethynyl derivative followed by theintroduction of a lactam-, cyclic carbamate- or cyclic urea usingprocedures similar to those described in schemes 1 to 4. (scheme 6)

The compound of formula I as described herein as well as itspharmaceutically acceptable salt is used in the treatment or preventionof psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitivedisorders and memory deficits, chronic and acute pain, restricted brainfunction caused by bypass operations or transplants, poor blood supplyto the brain, spinal cord injuries, head injuries, hypoxia caused bypregnancy, cardiac arrest and hypoglycaemia, ischemia, Huntington'schorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS,eye injuries, retinopathy, idiopathic parkinsonism or parkinsonismcaused by medicaments, muscle spasms, convulsions, migraine, urinaryincontinence, gastrointestinal reflux disorder, liver damage or failurewhether drug or disease induced, Fragile-X syndrom, Down syndrom,autism, nicotine addiction, opiate addiction, anxiety, vomiting,dyskinesia, eating disorders, in particular bulimia or anorexia nervosa,and depressions, particularly for the treatment and prevention of acuteand/or chronic neurological disorders, anxiety, the treatment of chronicand acute pain, urinary incontinence and obesity.

The preferred indications are schizophrenia and cognitive disorders.

Present invention further relates to the use of a compound of formula Ias described herein, as well as its pharmaceutically acceptable salt,for the manufacture of a medicament, preferably for the treatment andprevention of the above-mentioned disorders.

Biological Assay and Data Intracellular Ca²⁺ Mobilization Assay

A monoclonal HEK-293 cell line stably transfected with a cDNA encodingfor the human mGlu5a receptor was generated; for the work with mGlu5Positive Allosteric Modulators (PAMs), a cell line with low receptorexpression levels and low constitutive receptor activity was selected toallow the differentiation of agonistic versus PAM activity. Cells werecultured according to standard protocols (Freshney, 2000) in Dulbecco'sModified Eagle Medium with high glucose supplemented with 1 mMglutamine, 10% (vol/vol) heat-inactivated bovine calf serum,Penicillin/Streptomycin, 50 μg/ml hygromycin and 15 μg/ml blasticidin(all cell culture reagents and antibiotics from Invitrogen, Basel,Switzerland).

About 24 hrs before an experiment, 5×10⁴ cells/well were seeded inpoly-D-lysine coated, black/clear-bottomed 96-well plates. The cellswere loaded with 2.5 μM Fluo-4AM in loading buffer (1×HBSS, 20 mM HEPES)for 1 hr at 37° C. and washed five times with loading buffer. The cellswere transferred into a Functional Drug Screening System 7000(Hamamatsu, Paris, France), and 11 half logarithmic serial dilutions oftest compound at 37° C. were added and the cells were incubated for10-30 min. with on-line recording of fluorescence. Following thispre-incubation step, the agonist L-glutamate was added to the cells at aconcentration corresponding to EC₂₀ (typically around 80 μM) withon-line recording of fluorescence; in order to account for day-to-dayvariations in the responsiveness of cells, the EC₂₀ of glutamate wasdetermined immediately ahead of each experiment by recording of a fulldose-response curve of glutamate.

Responses were measured as peak increase in fluorescence minus basal(i.e. fluorescence without addition of L-glutamate), normalized to themaximal stimulatory effect obtained with saturating concentrations ofL-glutamate. Graphs were plotted with the % maximal stimulatory usingXLfit, a curve fitting program that iteratively plots the data usingLevenburg Marquardt algorithm. The single site competition analysisequation used was y=A+((B−A)/(1+((x/C)D))), where y is the % maximalstimulatory effect, A is the minimum y, B is the maximum y, C is theEC₅₀, x is the log 10 of the concentration of the competing compound andD is the slope of the curve (the Hill Coefficient). From these curvesthe EC₅₀ (concentration at which half maximal stimulation was achieved),the Hill coefficient as well as the maximal response in % of the maximalstimulatory effect obtained with saturating concentrations ofL-glutamate were calculated.

Positive signals obtained during the pre-incubation with the PAM testcompounds (i.e. before application of an EC₂₀ concentration ofL-glutamate) were indicative of an agonistic activity, the absence ofsuch signals were demonstrating the lack of agonistic activities. Adepression of the signal observed after addition of the EC₂₀concentration of L-glutamate was indicative of an inhibitory activity ofthe test compound.

In the list of examples below are shown the corresponding results forcompounds which all have

EC₅₀<300 nM.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof can be used as medicaments, e.g. in the form of pharmaceuticalcompositions. The pharmaceutical compositions can be administeredorally, e.g. in the form of tablets, coated tablets, dragées, hard andsoft gelatin capsules, solutions, emulsions or suspensions. However, theadministration can also be effected rectally, e.g. in the form ofsuppositories, or parenterally, e.g. in the form of injectablesolutions.

The present invention also provides pharmaceutical compositionscontaining compounds of the invention, for example, compounds of formulaI or pharmaceutically acceptable salts thereof and a pharmaceuticallyacceptable carrier. Such pharmaceutical compositions can be in the formof tablets, coated tablets, dragées, hard and soft gelatin capsules,solutions, emulsions or suspensions. The pharmaceutical compositionsalso can be in the form of suppositories or injectable solutions.

The pharmaceutical compositions of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic or organic carriers. lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts and thelike, for example, as such carriers for tablets, coated tablets, dragéesand hard gelatin capsules. Suitable carriers for soft gelatin capsulesare, for example, vegetable oils, waxes, fats, semi-solid and liquidpolyols and the like; depending on the nature of the active substance nocarriers are, however, usually required in the case of soft gelatincapsules. Suitable carriers for the production of solutions and syrupsare, for example, water, polyols, sucrose, invert sugar, glucose and thelike. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils andthe like, can be used for aqueous injection solutions of water-solublesalts of compounds of formula (I), but as a rule are not necessary.Suitable carriers for suppositories are, for example, natural orhardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical compositions can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

As mentioned earlier, medicaments containing a compound of formula (I)or pharmaceutically acceptable salts thereof and a therapeutically inertexcipient are also an object of the present invention, as is a processfor the production of such compositions which comprises bringing one ormore compounds of formula I or pharmaceutically acceptable salts thereofand, if desired, one or more other therapeutically valuable substancesinto a galenical dosage form together with one or more therapeuticallyinert carriers.

As further mentioned earlier, the use of the compounds of formula (I)for the preparation of pharmaceutical compositions useful in theprevention and/or the treatment of the above-recited diseases is also anaspect of the present invention.

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, the effective dosagefor oral or parenteral administration is between 0.01-20 mg/kg/day, witha dosage of 0.1-10 mg/kg/day being preferred for all of the indicationsdescribed. The daily dosage for an adult human being weighing 70 kgaccordingly lies between 0.7-1400 mg per day, preferably between 7 and700 mg per day.

Preparation of Pharmaceutical Compositions Comprising Compounds of theInvention:

Tablets of the following composition are produced in a conventionalmanner:

mg/Tablet Active ingredient 100 Powdered. lactose 95 White corn starch35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10 Magnesium stearate 2Tablet weight 250

LIST OF EXAMPLES

EC₅₀ (nM) Ex. Structure Name mGlu5PAM Eff. (%) 1

3-(3-Fluoro-5- phenylethynyl-pyridin- 2-yl)-5,5-dimethyl-oxazolidin-2-one 30 68 2

(5RS)-5- Methoxymethyl-3-(5- phenylethynyl-pyridin-2-yl)-oxazolidin-2-one 47 34 3

(5R or 5S)-5- Methoxymethyl-3-(5- phenylethynyl-pyridin-2-yl)-oxazolidin-2-one 18 46

4

(5S or 5R)-5- Methoxymethyl-3-(5- phenylethynyl-pyridin-2-yl)-oxazolidin-2- 278 98

5

5,5-Dimethyl-3-(5- phenylethynyl-pyridin- 2-yl)-oxazolidin-2-one 7 77 6

3-[5-(3-Fluoro- phenylethynyl)-pyridin- 2-yl]-5,5-dimethyl-oxazolidin-2-one 9 46 7

5,5-Dimethyl-3-(5- pyridin-3-ylethynyl- pyridin-2-yl)- oxazolidin-2-one33 39 8

(5RS)-5-tert-Butyl-3- (5-phenylethynyl- pyridin-2-yl)- oxazolidin-2-one17 62 9

6-(5-Phenylethynyl- pyridin-2-yl)-4-oxa-6- aza-spiro[2.4]heptan-5- one15 83 10

7-(5-Phenylethynyl- pyridin-2-yl)-5-oxa-7- aza-spiro[3.4]octan-6- one 25109 11

3-(5-Phenylethynyl- pyridin-2-yl)-1-oxa-3- aza-spiro[4.4]nonan-2- one 3952 12

3-(5-Phenylethynyl- pyridin-2-yl)-1-oxa-3- aza-spiro[4.5]decan-2- one 6780 13

4,4-Dimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-pyrrolidin-2-one 37 12914

(3RS)-3-Hydroxy-4,4- dimethyl-1-(5- phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one 388 114 15

4,4-Dimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-imidazolidin-2- one 130101 16

3,4,4-Trimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-imidazolidin-2- one35 103 17

3-Ethyl-4,4-dimethyl-1- (5-phenylethynyl- pyridin-2-yl)-imidazolidin-2-one 66 103 18

3-Isopropyl-4,4- dimethyl-1-(5- phenylethynyl-pyridin-2-yl)-imidazolidin-2- one 39 133 19

(5RS)-5-tert-Butyl-5- methyl-3-(5- phenylethynyl-pyridin-2-yl)-oxazolidin-2-one 27 85 20

5,5-Dimethyl-3-(5- phenylethynyl-pyridin- 2-yl)-[1,3]oxazinan-2- one 27135 21

1-(3-Fluoro-5- phenylethynyl-pyridin- 2-yl)-4,4-dimethyl-pyrrolidin-2-one 30 128 22

(3aRS,6aSR)-3-(5- Phenylethynyl-pyridin- 2-yl)-hexahydro-cyclopentaoxazol-2-one 14 74 23

(3aRS,6aSR)-3-(5- Pyridin-3-ylethynyl- pyridin-2-yl)- hexahydro-cyclopentaoxazol-2-one 12 92 24

(3aRS,6aSR)-3-[5-(5- Fluoro-pyridin-3- ylethynyl)-pyridin-2-yl]-hexahydro- cyclopentaoxazol-2-one 35 73 25

5,5-Dimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-tetrahydro-pyrimidin-2-one 69 148 26

1,5,5-Trimethyl-3-(5- phenylethynyl-pyridin- 2-yl)-tetrahydro-pyrimidin-2-one 33 131 27

(RS)-4,5,5-Trimethyl-3- (5-phenylethynyl- pyridin-2-yl)-oxazolidin-2-one 15 61 28

4,4,5,5-Tetramethyl-3- (5-phenylethynyl- pyridin-2-yl)- oxazolidin-2-one48 31 29

3-[5-(5-Fluoro-pyridin- 3-ylethynyl)-pyridin-2- yl]-5,5-dimethyl-oxazolidin-2-one 15 45 30

5,5-Dimethyl-3-(5- pyrimidin-5-ylethynyl- pyridin-2-yl)-oxazolidin-2-one 80 43 31

5,5-Dimethyl-3-[5-(1- methyl-1H-pyrazol-4- ylethynyl)-pyridin-2-yl]oxazolidin-2-one 26 55 32

3-[5-(4-Fluoro- phenylethynyl)-pyridin- 2-yl]-5,5-dimethyl-oxazolidin-2-one 19 60 33

3-[5-(3,4-Difluoro- phenylethynyl)-pyridin- 2-yl]-5,5-dimethyl-oxazolidin-2-one 32 44 34

3-[5-(2,5-Difluoro- phenylethynyl)-pyridin- 2-yl]-5,5-dimethyl-oxazolidin-2-one 11 38 35

3-[5-(6-Fluoro-pyridin- 3-ylethynyl)-pyridin-2- yl]-5,5-dimethyl-oxazolidin-2-one 54 52 36

6-(5-Pyridin-3- ylethynyl-pyridin-2-yl)- 4-oxa-6-aza-spiro[2.4]heptan-5-one 58 80 37

1-[5-(5-Fluoro-pyridin- 3-ylethynyl)-pyridin-2- yl]-4,4-dimethyl-pyrrolidin-2-one 22 96 38

4,4-Dimethyl-1-(5- pyridin-3-ylethynyl- pyridin-2-yl)- pyrrolidin-2-one33 147 39

1-[5-(5-Chloro-pyridin- 3-ylethynyl)-pyridin-2- yl]-4,4-dimethyl-pyrrolidin-2-one 48 98 40

1-[5-(3-Fluoro- phenylethynyl)-pyridin- 2-yl]-4,4-dimethyl-pyrrolidin-2-one 15 100 41

4,4-Dimethyl-1-(3- methyl-5- phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one 58 89 42

5,5-Dimethyl-5′- phenylethynyl-3,4,5,6- tetrahydro-[1,2′]bipyridinyl-2-one 16 139 43

5′-(3-Fluoro- phenylethynyl)-5,5- dimethyl-3,4,5,6- tetrahydro-[1,2′]bipyridinyl-2-one 12 100 44

1-Methyl-3-(5- phenylethynyl-pyridin- 2-yl)-1,3-diaza-spiro[4.4]nonan-2-one 29 92 45

(RS)-4-Cyclopentyl-3- methyl-1-(5- phenylethynyl-pyridin-2-yl)-imidazolidin-2- one 57 97 46

(1RS,5SR)-6-(5- Phenylethynyl-pyridin- 2-yl)-6-aza-bicyclo[3.2.0]heptan-7- one 26 27 47

(6SR,7RS)-3-(5- Phenylethynyl-pyridin- 2-yl)-hexahydro-benzooxazol-2-one 36 109 48

3,4,4-Trimethyl-1-(5- pyridin-3-ylethynyl- pyridin-2-yl)-imidazolidin-2-one 14 89 49

1-[5-(5-Fluoro-pyridin- 3-ylethynyl)-pyridin-2- yl]-3,4,4-trimethyl-imidazolidin-2-one 37 91 50

3,4,4-Trimethyl-1-[5- (1-methyl-1H-pyrazol- 4-ylethynyl)-pyridin-2-yl]-imidazolidin-2-one 27 41 51

1-[5-(5-Chloro-pyridin- 3-ylethynyl)-pyridin-2- yl]-3,4,4-trimethyl-imidazolidin-2-one 29 45 52

3,4,4-Trimethyl-1-(5- pyridazin-4-ylethynyl- pyridin-2-yl)-imidazolidin-2-one 34 32 53

1-[5-(3-Fluoro- phenylethynyl)-pyridin- 2-yl]-3,4,4-trimethyl-imidazolidin-2-one 29 103 54

1-[5-(3-Chloro- phenylethynyl)-pyridin- 2-yl]-3,4,4-trimethyl-imidazolidin-2-one 32 47 55

3,4,4-Trimethyl-1-(5- pyrimidin-5-ylethynyl- pyridin-2-yl)-imidazolidin-2-one 54 110 56

3,4,4-Trimethyl-1-(5- m-tolylethynyl-pyridin- 2-yl)-imidazolidin-2- one87 56 57

1-[5-(4-Fluoro- phenylethynyl)-pyridin- 2-yl]-3,4,4-trimethyl-imidazolidin-2-one 35 78 58

(RS)-2-(5- Phenylethynyl-pyridin- 2-yl)-hexahydro-imidazo[1,5-a]pyridin- 3-one 33 43 59

2-(5-Phenylethynyl- pyridin-2-yl)-2-aza- spiro[4.4]nonan-3-one 16 81 60

(RS)-3-Methoxy-4,4- dimethyl-1-(5- phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one 35 89 61

(R or S)-3-Methoxy- 4,4-dimethyl-1-(5- phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one 75 70 62

(S or R)-3-Methoxy- 4,4-dimethyl-1-(5- phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one 12 86 63

(RS)-1-[5-(5-Chloro- pyridin-3-ylethynyl)- pyridin-2-yl]-3-methoxy-4,4-dimethyl- pyrrolidin-2-one 70 99 64

(RS)-3-Methoxy-4,4- dimethyl-1-(5-m- tolylethynyl-pyridin-2-yl)-pyrrolidin-2-one 87 56 65

(RS)-1-[5-(3-Fluoro- phenylethynyl)-pyridin- 2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2- one 43 91 66

(RS)-1-[5-(4-Fluoro- phenylethynyl)-pyridin- 2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2- one 75 87 67

3,4,4-Trimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-tetrahydro-pyrimidin-2-one 15 81 68

1-[5-(2,5-Difluoro- phenylethynyl)-pyridin- 2-yl]-3,4,4-trimethyl-tetrahydro-pyrimidin-2- one 41 79 69

1-[5-(4-Fluoro- phenylethynyl)-pyridin- 2-yl]-3,4,4-trimethyl-tetrahydro-pyrimidin-2- one 49 107 70

(RS)-2-(5-Pyridin-3- ylethynyl-pyridin-2-yl)- hexahydro-imidazo[1,5-a]pyridin-3-one 74 51 71

(RS)-2-[5-(3-Fluoro- phenylethynyl)-pyridin- 2-yl]-hexahydro-imidazo[1,5-a]pyridin- 3-one 17 41 72

6,6-Dimethyl-3-(5- phenylethynyl-pyridin- 2-yl)-[1,3]oxazinan-2- one 1086 73

6,6-Dimethyl-3-(5- pyridin-3-ylethynyl- pyridin-2-yl)-[1,3]oxazinan-2-one 59 98 74

3-[5-(5-Fluoro-pyridin- 3-ylethynyl)-pyridin-2- yl]-6,6-dimethyl-[1,3]oxazinan-2-one 59 108 75

3-[5-(5-Chloro-pyridin- 3-ylethynyl)-pyridin-2- yl]-6,6-dimethyl-[1,3]oxazinan-2-one 27 87 76

3-[5-(3-Fluoro- phenylethynyl)-pyridin- 2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one 13 124 77

3-[5-(3-Chloro- phenylethynyl)-pyridin- 2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one 12 72 78

6,6-Dimethyl-3-(5-m- tolylethynyl-pyridin-2- yl)-[1,3]oxazinan-2-one 2472 79

3-[5-(4-Fluoro- phenylethynyl)-pyridin- 2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one 22 85 80

3-[5-(3,4-Difluoro- phenylethynyl)-pyridin- 2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one 37 69 81

3-[5-(2,5-Difluoro- phenylethynyl)-pyridin- 2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one 12 95 82

6-(5-Phenylethynyl- pyridin-2-yl)-2-oxa-6- aza-spiro[3.4]octan-7- one 5772 83

(RS)-4-Cyclopropyl-3- methyl-1-(5- phenylethynyl-pyridin-2-yl)-imidazolidin-2- one 53 86 84

(3aSR,7aRS)- (3aRS,7RS)-1-Methyl- 3-(5-phenylethynyl- pyridin-2-yl)-octahydro- benzoimidazol-2-one 11 64 85

(3aSR,7aRS)- (3aRS,7RS)-1-Methyl- 3-(5-pyridin-3-ylethynyl-pyridin-2-yl)- octahydro- benzoimidazol-2-one 27 49 86

(3aSR,7aRS)- (3aRS,7RS)-1-[5-(5- Fluoro-pyridin-3- ylethynyl)-pyridin-2-yl]-3-methyl-octahydro- benzoimidazol-2-one 32 52 87

4,4-Dimethyl-5′- phenylethynyl-3,4,5,6- tetrahydro-[1,2′]bipyridinyl-2-one 12 89 88

5′-(3-Fluoro- phenylethynyl)-4,4- dimethyl-3,4,5,6- tetrahydro-[1,2′]bipyridinyl-2-one 19 110 89

5′-(3-Chloro- phenylethynyl)-4,4- dimethyl-3,4,5,6- tetrahydro-[1,2′]bipyridinyl-2-one 25 78 90

5′-(5-Chloro-pyridin-3- ylethynyl)-4,4- dimethyl-3,4,5,6- tetrahydro-[1,2′]bipyridinyl-2-one 66 90 91

5′-(4-Fluoro- phenylethynyl)-4,4- dimethyl-3,4,5,6- tetrahydro-[1,2′]bipyridinyl-2-one 67 89 92

5′-(2,5-Difluoro- phenylethynyl)-4,4- dimethyl-3,4,5,6- tetrahydro-[1,2′]bipyridinyl-2-one 32 84 93

7,7-Dimethyl-3-(5- phenylethynyl-pyridin- 2-yl)-[1,3]oxazepan-2- one 36104 94

(3aSR,7aRS)- (3aRS,7RS)-1-(5- Phenylethynyl-pyridin- 2-yl)-hexahydro-pyrano[4,3-d]oxazol-2- one 60 84 95

(RS)-5-Hydroxy-6,6- dimethyl-3-(5- phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2- one 47 118 96

4-Methyl-6-(5- phenylethynyl-pyridin- 2-yl)-4,6-diaza-spiro[2.4]heptan-5-one 35 98 97

3,3-Dimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-azetidin-2-one 36 71 98

(1RS,5SR)-6-(5- Pyridin-3-ylethynyl- pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7- one 39 73 99

(3aSR,7aRS)- (3aRS,7RS)-1-Ethyl-3- (5-phenylethynyl- pyridin-2-yl)-octahydro- benzoimidazol-2-one 18 90 100

(3aSR,7aRS)- (3aRS,7RS)-1-Ethyl-3- (5-pyridin-3-ylethynyl-pyridin-2-yl)- octahydro- benzoimidazol-2-one 69 64 101

(3aSR,7aRS)- (3aRS,7RS)-1- Isopropyl-3-(5- phenylethynyl-pyridin-2-yl)-octahydro- benzoimidazol-2-one 39 77 102

(4aRS,7aSR)-3-(5- Phenylethynyl-pyridin- 2-yl)-hexahydro-cyclopenta[e][1,3]oxazin- 2-one 43 115 103

(4aRS,7aRS)-3-(5- Phenylethynyl-pyridin- 2-yl)-hexahydro-cyclopenta[e][1,3]oxazin- 2-one 27 123 104

(RS)-5,6,6-Trimethyl-3- (5-phenylethynyl- pyridin-2-yl)-[1,3]oxazinan-2-one 42 109 105

(RS)-6- Methoxymethyl-3-(5- phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2- one 68 51 106

(3aRS,6aSR)-1-Methyl- 3-(5-(phenylethynyl) pyridin-2-yl)hexa-hydrocyclopenta[d] imidazol-2(1H)-one 30 42 107

(RS)-4-tert-Butyl-3- methyl-1-(5- phenylethynyl-pyridin-2-yl)-imidazolidin-2- one 59 106 108

1-[5-(3-Fluoro- phenylethynyl)-3- methyl-pyridin-2-yl]- 3,4,4-trimethyl-imidazolidin-2-one 102 115 109

(3aRS, 6aSR)-1-[5-(3- Fluoro-phenylethynyl)- pyridin-2-yl]-3-methyl-hexahydro-cyclopenta- imidazol-2-one 18 37 110

1-[3-Fluoro-5-(4- fluoro-phenylethynyl)- pyridin-2-yl]-3,4,4-trimethyl-imidazolidin- 2-one 96 117 111

1-[3-Fluoro-5-(3- fluoro-phenylethynyl)- pyridin-2-yl]-3,4,4-trimethyl-imidazolidin- 2-one 32 107 112

6-[5-(4-Fluoro- phenylethynyl)-pyridin- 2-yl]-4-methyl-4,6-diaza-spiro[2.4]heptan- 5-one 80 89 113

6-[5-(3-Fluoro- phenylethynyl)-pyridin- 2-yl]-4-methyl-4,6-diaza-spiro[2.4]heptan- 5-one 51 75 114

(RS)-5-Methoxy-6,6- dimethyl-3-(5- phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2- one 22 57 115

4,4-Dimethyl-1-(5- phenylethynyl- pyrimidin-2-yl)- pyrrolidin-2-one 13109 116

5,5-Dimethyl-1-(5- phenylethynyl- pyrimidin-2-yl)- piperidin-2-one 41101 117

2-(5-Phenylethynyl- pyrimidin-2-yl)-2-aza- spiro[4.4]nonan-3-one 44 84118

1-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2- one 13 78 119

1-[5-(3-Chloro- phenylethynyl)- pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2- one 11 26 120

1-[5-(4-Fluoro- phenylethynyl)- pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2- one 92 81 121

1-[5-(2,5-Difluoro- phenylethynyl)- pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2- one 41 70 122

3,4,4-Trimethyl-1-(5- phenylethynyl- pyrimidin-2-yl)- imidazolidin-2-one11 36 123

1-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin- 2-one 18 30 124

1-[5-(2,5-Difluoro- phenylethynyl)- pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin- 2-one 7 43 125

1-[5-(4-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin- 2-one 13 44 126

1-[5-(3,4-Difluoro- phenylethynyl)- pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin- 2-one 23 36 127

(RS)-3-Methoxy-4,4- dimethyl-1-(5- phenylethynyl- pyrimidin-2-yl)-pyrrolidin-2-one 29 94 128

(R or S)-3-Methoxy- 4,4-dimethyl-1-(5- phenylethynyl- pyrimidin-2-yl)-pyrrolidin-2-one 46 54 129

(S or R)-3-Methoxy- 4,4-dimethyl-1-(5- phenylethynyl- pyrimidin-2-yl)-pyrrolidin-2-one 18 90 130

(RS)-1-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3-methoxy-4,4-dimethyl- pyrrolidin-2-one 41 74 131

(R or S)-1-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3-methoxy-4,4-dimethyl- pyrrolidin-2-one 35 48

132

(S or R)-1-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3-methoxy-4,4-dimethyl- pyrrolidin-2-one 21 69

133

(R or S)-1-[5-(2,5- Difluoro- phenylethynyl)- pyrimidin-2-yl]-3-methoxy-4,4-dimethyl- pyrrolidin-2-one 57 49

134

4,4-Dimethyl-1-(5- phenylethynyl- pyrimidin-2-yl)- piperidin-2-one 42 90135

1-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-4,4-dimethyl-piperidin-2- one 35 47 136

1-[5-(2,5-Difluoro- phenylethynyl)- pyrimidin-2-yl]-4,4-dimethyl-piperidin-2- one 31 49 137

3,4,4-Trimethyl-5′- phenylethynyl-3,4,5,6- tetrahydro-[1,2′]bipyrimidinyl-2- one 66 74 138

5′-(3-Fluoro- phenylethynyl)-3,4,4- trimethyl-3,4,5,6- tetrahydro-[1,2′]bipyrimidinyl-2- one 60 67 139

5′-(2,5-Difluoro- phenylethynyl)-3,4,4- trimethyl-3,4,5,6- tetrahydro-[1,2′]bipyrimidinyl-2- one 57 54 140

3-Isopropyl-4,4- dimethyl-1-(5- phenylethynyl- pyrimidin-2-yl)-imidazolidin-2-one 28 58 141

1-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3-isopropyl-4,4-dimethyl- imidazolidin-2-one 28 39 142

1-[5-(4-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3-isopropyl-4,4-dimethyl- imidazolidin-2-one 78 74 143

1-[5-(4-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3-ethyl- 4,4-dimethyl-imidazolidin-2-one 47 68 144

1-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3-ethyl- 4,4-dimethyl-imidazolidin-2-one 31 58 145

(RS)-5,6,6-Trimethyl-3- (5-phenylethynyl- pyrimidin-2-yl)-[1,3]oxazinan-2-one 38 93 146

(RS)-3-[5-(2,5- Difluoro- phenylethynyl)- pyrimidin-2-yl]-5,6,6-trimethyl- [1,3]oxazinan-2-one 69 64 147

4-Methyl-6-(5- phenylethynyl- pyrimidin-2-yl)-4,6-diaza-spiro[2.4]heptan- 5-one 25 36 148

(RS)-3-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-5,6,6- trimethyl-[1,3]oxazinan-2-one 39 75 149

(RS)-3-[5-(4-Fluoro- phenylethynyl)- pyrimidin-2-yl]-5,6,6- trimethyl-[1,3]oxazinan-2-one 114 78 150

4,4-dimethyl-1-(6- (phenylethynyl) pyridazin-3-yl) pyrrolidin-2-one 21113 151

4,4-dimethyl-1-(6- (phenylethynyl)pyridazin- 3-yl)piperidin-2-one 19 130152

5,5-dimethyl-3-(6- (phenylethynyl)pyridazin- 3-yl)oxazolidin-2-one 15112 153

6,6-dimethyl-3-(6- (phenylethynyl)pyridazin- 3-yl)-1,3-oxazinan-2- one14 86 154

3,4,4-trimethyl-1-(6- (m- tolylethynyl)pyridazin-3-yl)imidazolidin-2-one 61 108 155

1-(6-((3- chlorophenyl)ethynyl) pyridazin-3-yl)-3,4,4-trimethylimidazolidin- 2-one 73 95 156

3,4,4-trimethyl-1-(5- (phenylethynyl)pyrazin- 2-yl)imidazolidin-2-one 2458 157

3,4,4-trimethyl-1-(5- (pyridin-3- ylethynyl)pyrazin-2-yl)imidazolidin-2-one 206 34 158

1-(5-((3- fluorophenyl)ethynyl) pyrazin-2-yl)-3,4,4-trimethylimidazolidin- 2-one 46 36 159

1-[5-(4-Fluoro- phenylethynyl)-pyrazin- 2-yl]-3,4,4-trimethyl-imidazolidin-2-one 49 49 160

1-(5-((3- fluorophenyl)ethynyl) pyrazin-2-yl)-4,4- dimethylpyrrolidin-2-one 29 39 161

1-(5-((3- fluorophenyl)ethynyl) pyrazin-2-yl)-4,4- dimethylpiperidin-2-one 29 68 162

4,4-dimethyl-1-(5- (pyridin-3- ylethynyl)pyrazin-2- yl)piperidin-2-one681 76 163

4,4-dimethyl-1-(5- (phenylethynyl)pyrazin- 2-yl)piperidin-2-one 69 74164

4,4-dimethyl-1-(5- (phenylethynyl)pyrazin- 2-yl)tetrahydro-pyrimidin-2(1H)-one 329 89 165

3,4,4-trimethyl-1-(5- (phenylethynyl)pyrazin- 2-yl)tetrahydro-pyrimidin-2(1H)-one 36 55 166

1-(5-((3- fluorophenyl)ethynyl) pyrazin-2-yl)-4,4- dimethyltetrahydro-pyrimidin-2(1H)-one 140 56 167

1-(5-((3- fluorophenyl)ethynyl) pyrazin-2-yl)-3,4,4-trimethyltetrahydro- pyrimidin-2(1H)-one 26 54 168

6,6-dimethyl-3-(5- (phenylethynyl)pyrazin- 2-yl)-1,3-oxazinan-2- one 1541 169

(RS)-3-[5-(3-Fluoro- phenylethynyl)-pyridin- 2-yl]-5-methoxy-6,6-dimethyl- [1,3]oxazinan-2-one 13 52 170

(3aRS,6aSR)-1-Methyl- 3-(6-phenylethynyl- pyridazin-3-yl)- hexahydro-cyclopentaimidazol-2- one 13 105 171

(RS)-6-Methyl-4-(5- phenylethynyl-pyridin- 2-yl)-morpholin-3-one 88 73172

6,6-Dimethyl-4-(5- phenylethynyl-pyridin- 2-yl)-morpholin-3-one 29 82173

1,1-Dioxo-4-(5- phenylethynyl-pyridin- 2-yl)-thiomorpholin-3- one 29 82174

(3aRS,6aSR)-1-[6-(3- Fluoro-phenylethynyl)- pyridazin-3-yl]-3-methyl-hexahydro- cyclopentaimidazol-2- one 12 56

Experimental Section Example 13-(3-Fluoro-5-phenylethynyl-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one

Step 1: 1-(3-Fluoro-5-iodo-pyridin-2-ylamino)-2-methyl-propan-2-ol

2,3-Difluoro-5-iodopyridine (500 mg, 2.07 mmol) was dissolved in NMP(500 μL) and pyridine (201 μl, 2.49 mmol, 1.2 equiv.) and1-amino-2-methylpropan-2-ol (555 mg, 6.22 mmol, 3 equiv.) were added atroom temperature. The mixture was stirred for 16 hours at 100° C. Thereaction mixture was cooled and extracted with saturated NaHCO₃ solutionand two times with a small volume of dichloromethane. The crude productwas purified by flash chromatography by directly loading thedichloromethane layers onto a silica gel column and eluting with anethyl acetate:heptane gradient 0:100 to 100:0. The desired1-(3-fluoro-5-iodopyridin-2-ylamino)-2-methylpropan-2-ol (590 mg, 1.9mmol, 91.7% yield) was obtained as a colorless oil, MS: m/e=311.0(M+H⁺).

Step 2: 3-(3-Fluoro-5-iodopyridin-2-yl)-5,5-dimethyloxazolidin-2-one

(580 mg, 1.87 mmol)1-(3-Fluoro-5-iodopyridin-2-ylamino)-2-methylpropan-2-ol (Example 1,step 1) was dissolved in dichloromethane (10 ml) and pyridine (300 μl,3.74 mmol, 2 equiv.) was added at room temperature. The mixture wascooled to 0-5° C. and phosgene (20% in toluene) (1.19 ml, 2.24 mmol, 1.2equiv.) was added dropwise over a period of 15 min at 0-5° C. Themixture was stirred for 1 hour at 0-5° C. The reaction mixture wasextracted with saturated NaHCO₃ solution and two times with a smallvolume of dichloromethane. The crude product was purified by flashchromatography by directly loading the dichloromethane layers onto asilica gel column and eluting with a heptane:ethyl acetate gradient100:0 to 50:50. The desired3-(3-fluoro-5-iodopyridin-2-yl)-5,5-dimethyloxazolidin-2-one (500 mg,1.49 mmol, 79.5% yield) was obtained as a white solid, MS: m/e=337.0(M+H⁺).

Step 3:3-(3-Fluoro-5-phenylethynyl-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one

Bis-(triphenylphosphine)-palladium(II)dichloride (12.5 mg, 17.9 μmol,0.05 equiv.) was dissolved in 1 ml DMF. (120 mg, 357 μmol)3-(3-Fluoro-5-iodopyridin-2-yl)-5,5-dimethyloxazolidin-2-one (Example 1,step 2) and phenylacetylene (72.9 mg, 78.4 μl, 714 μmol, 2 equiv.) wereadded at room temperature. Triethylamine (108 mg, 149 μl, 1.07 mmol, 3equiv.), triphenylphosphine (2.81 mg, 10.7 μmol, 0.03 equiv.) andcopper(I)iodide (2.04 mg, 10.7 μmol, 0.03 equiv.) were added and themixture was stirred for 3 hours at 70° C. The reaction mixture wascooled and extracted with saturated NaHCO₃ solution and two times with asmall volume of dichloromethane. The crude product was purified by flashchromatography by directly loading the dichloromethane layers onto asilica gel column and eluting with an ethyl acetate:heptane gradient0:100 to 40:60. The desired3-(3-fluoro-5-(phenylethynyl)pyridin-2-yl)-5,5-dimethyloxazolidin-2-one(96 mg, 309 μmol, 86.6% yield) was obtained as a yellow solid, MS:m/e=311.2 (M+H⁺).

Example 2(5RS)-5-Methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound, a light brown solid, MS: m/e=309.1 (M+H⁺), wasprepared using a procedure similar to that described in Example 1, step3 from 3-(5-bromo-pyridin-2-yl)-5-methoxymethyl-oxazolidin-2-one (CAS170011-45-7) and phenylacetylene.

Example 3 (5R or5S)-5-Methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound, a white solid, MS: m/e=309.1 (M+H⁺), was prepared byseparation of(5RS)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one(Example 2) using a chiral column (chiralpak AD with heptane:isopropanol80:20 as solvent).

Example 4 (5S or5R)-5-Methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound, a white solid, MS: m/e=309.1 (M+H⁺), was prepared byseparation of(5RS)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one(Example 2) using a chiral column (chiralpak AD with heptane:isopropanol80:20 as solvent).

Example 5 5,5-Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

Step 1: 3-(5-Iodo-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=292.9 (M+H⁺),using procedures similar to those described in Example 1, step 1 andstep 2 from 2-fluoro-5-iodopyridine and 1-amino-2-methylpropan-2-ol.

Step 2: 5,5-Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=293.0 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from3-(5-iodo-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one (Example 5,step 1) and phenylacetylene.

Example 63-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=311.2 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from3-(5-iodo-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one (Example 5,step 1) and 3-fluorophenylacetylene.

Example 75,5-Dimethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=294.1 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from3-(5-iodo-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one (Example 5,step 1) and 3-ethynyl-pyridine.

Example 8(5RS)-5-tert-Butyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

Step 1: (5RS)-5-tert-Butyl-3-(5-iodo-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=346.9 (M+H⁺),using procedures similar to those described in Example 1, step 1 andstep 2 from 2-fluoro-5-iodopyridine and(rac)-1-amino-3,3-dimethylbutan-2-ol hydrochloride.

Step 2:(5RS)-5-tert-Butyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=321.2 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from(5RS)-5-tert-butyl-3-(5-iodo-pyridin-2-yl)-oxazolidin-2-one (Example 8,step 1) and phenylacetylene.

Example 96-(5-Phenylethynyl-pyridin-2-yl)-4-oxa-6-aza-spiro[2.4]heptan-5-one

The title compound was obtained as a colourless solid, MS: m/e=291.2(M+H⁺), using procedures similar to those described in Example 1starting from 2-fluoro-5-bromopyridine, 1-aminomethyl-cyclopropanol(Russian J. Org. Chem. 2001, 37, 1238) and phenylacetylene.

Example 107-(5-Phenylethynyl-pyridin-2-yl)-5-oxa-7-aza-spiro[3.4]octan-6-one

The title compound was obtained as a light yellow solid, MS: m/e=305.2(M+H⁺), using procedures similar to those described in Example 1starting from 2-fluoro-5-bromopyridine, 1-aminomethyl-cyclobutanol(WO2006/29115 A2) and phenylacetylene.

Example 113-(5-Phenylethynyl-pyridin-2-yl)-1-oxa-3-aza-spiro[4.4]nonan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=319.2(M+H⁺), using procedures similar to those described in Example 1starting from 2-fluoro-5-bromopyridine, 1-aminomethyl-cyclopentanol andphenylacetylene.

Example 123-(5-Phenylethynyl-pyridin-2-yl)-1-oxa-3-aza-spiro[4.5]decan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=333.2(M+H⁺), using procedures similar to those described in Example 1starting from 2-fluoro-6-bromopyridine, 1-aminomethyl-cyclohexanol andphenylacetylene.

Example 134,4-Dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

Step 1: 1-(5-Iodo-pyridin-2-yl)-3,3-dimethyl-pyrrolidine-2,5-dione

5-iodopyridin-2-amine (1 g, 4.55 mmol) was dissolved in DMF (5 ml) and3,3-dimethyldihydrofuran-2,5-dione (1.28 g, 10.0 mmol, 2.2 equiv.) wasadded at room temperature. The mixture was stirred for 3 hr at 150° C.The reaction mixture was evaporated to dryness and loaded directly to asilica gel column. The crude material was purified by flashchromatography on silica gel (20 gr, ethyl acetate/heptane gradient,0:100 to 100:0). The desired1-(5-iodopyridin-2-yl)-3,3-dimethylpyrrolidine-2,5-dione (1.3 g, 3.94mmol, 86.6% yield) was obtained as a yellow solid, MS: m/e=331.0 (M+H⁺).

Step 2:(5RS)-5-Hydroxy-1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one

(800 mg, 2.42 mmol)1-(5-Iodopyridin-2-yl)-3,3-dimethylpyrrolidine-2,5-dione (Example 13,step 1) was dissolved in THF (6 ml) and MeOH (2 ml) and the solution wascooled to 0-5° C. NaBH₄ (101 mg, 2.67 mmol, 1.1 equiv.) was added at0-5° C. and the mixture was stirred for 1 hr at 0-5° C. The reactionmixture was extracted with sat. NaHCO₃ solution and two times with asmall volume of dichloromethane. The crude product was purified by flashchromatography by directly loading the dichloromethane layers onto aamino-silica gel column and eluting with a ethyl acetate/heptanegradient, 0:100 to 100:0. The desired(5-RS)-5-hydroxy-1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one(370 mg, 46% yield) was obtained as a white solid, MS: m/e=333.0 (M+H⁺).

Step 3: 1-(5-Iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one

(275 mg, 828 μmol)(5RS)-5-Hydroxy-1-(5-iodopyridin-2-yl)-4,4-dimethylpyrrolidin-2-one(Example 13, step 2) was dissolved in CH₂Cl₂ (2 ml) and trifluoroaceticanhydride (140 μl, 994 μmol, 1.2 equiv.) was added at room temperature.The mixture was stirred for 1 hr at 20-25° C. The solution wasevaporated to dryness and the residue was dissolved in trifluoroaceticacid (957 μl, 12.4 mmol, 15 equiv.) and triethylsilane (159 μl, 994μmol, 1.2 equiv.) was added at room temperature. The mixture was stirred1 h at room temperature. The reaction mixture was evaporated andextracted with sat. NaHCO₃ solution and two times with a small volume ofdichloromethane. The crude product was purified by flash chromatographyby directly loading the dichloromethane layers onto a silica gel column(20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired1-(5-iodopyridin-2-yl)-4,4-dimethylpyrrolidin-2-one (209 mg, 80% yield)was obtained as a white solid, MS: m/e=317.0 (M+H⁺).

Step 4: 4,4-Dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a yellow oil, MS: m/e=291.1 (M+H⁺),using chemistry that is described in Example 1, step 3 from1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one (Example 13, step3) and phenylacetylene.

Example 14(3RS)-3-Hydroxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

Step 1: (4RS)-4-Hydroxy-3,3-dimethyl-dihydro-furan-2,5-dione

(3RS)-3-Hydroxy-2,2-dimethyl-succinic acid [Tetrahedron Letters (2002),43(52), 9513-9515] (120 mg, 0.74 mmol) was suspended in CH₂Cl₂ (2 ml)and cooled to 0-5° C. Trifluoroacetic anhydride (260 μl, 1.85 mmol) wasadded and the reaction mixture stirred for 2 hours at room temperature.The reaction mixture was evaporated to dryness and used without anyfurther purification in the next step.

Step 2:(4RS)-4-Hydroxy-1-(5-iodo-pyridin-2-yl)-3,3-dimethyl-pyrrolidine-2,5-dione

The title compound was obtained as a light yellow solid, MS: m/e=346.8(M+H⁺), using chemistry similar to that described in Example 12, step 1from 5-iodopyridin-2-amine and(4RS)-4-hydroxy-3,3-dimethyl-dihydro-furan-2,5-dione (Example 14, step1).

Step 3:(4RS)-4-(tert-Butyl-diphenyl-silanyloxy)-1-(5-iodo-pyridin-2-yl)-3,3-dimethyl-pyrrolidine-2,5-dione

(2.4 g, 3.47 mmol, 50%)(4RS)-4-Hydroxy-1-(5-iodo-pyridin-2-yl)-3,3-dimethyl-pyrrolidine-2,5-dione(Example 14, step 2) was dissolved in dichloromethane (20 ml). Imidazole(520 mg, 7.63 mmol) and tert-butyldiphenylchlorosilane (1.0 g, 3.64mmol) were added at room temperature and the mixture was stirred for 3hours at room temperature. Sat. NaHCO₃ solution was added and themixture was extracted with dichloromethane. The organic extracts weredried with sodium sulfate, filtered and evaporated. The crude productwas purified by flash chromatography on silica gel (ethylacetate/heptane gradient 0:100 to 30:70). The desired compound wasobtained as a white solid (1.5 g, 74% yield), MS: m/e=585.1 (M+H⁺).

Step 4:(3RS,5RS)-3-(tert-Butyl-diphenyl-silanyloxy)-5-hydroxy-1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=587.0(M+H⁺), using chemistry similar to that described in Example 12, step 2from(4RS)-4-(tert-butyl-diphenyl-silanyloxy)-1-(5-iodo-pyridin-2-yl)-3,3-dimethyl-pyrrolidine-2,5-dione(Example 14, step 3).

Step 5:(3RS)-3-(tert-Butyl-diphenyl-silanyloxy)-1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a colorless oil, MS: m/e=571.1(M+H⁺), using chemistry similar to that described in Example 12, step 3from(3RS,5RS)-3-(tert-butyl-diphenyl-silanyloxy)-5-hydroxy-1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one(Example 14, step 4).

Step 6:(3RS)-3-(tert-Butyl-diphenyl-silanyloxy)-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a brown oil, MS: m/e=545.3 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from(3RS)-3-(tert-butyl-diphenyl-silanyloxy)-1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one(Example 14, step 5) and phenylacetylene.

Step 7:(3RS)-3-Hydroxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

(100 mg, 0.18 mmol)(3RS)-3-(tert-Butyl-diphenyl-silanyloxy)-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one(Example 14, step 6) was dissolved in THF (1 ml) and TBAF (1M in THF)(184 μl, 0.184) was added drop wise at room temperature. The mixture wasstirred for 1 hr at 60° C. The reaction mixture was extracted with sat.NaHCO₃-solution and two times EtOAc. The organic layers were extractedwith water, dryed over Na₂SO₄, filtered and evaporated to dryness. Thecrude material was purified by flash chromatography on silica gel (20gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired(3RS)-3-hydroxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one(44 mg, 78% yield) was obtained as a white solid, MS: m/e=307.3 (M+H⁺).

Example 154,4-Dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one

Step 1: N-1-(5-Iodo-pyridin-2-yl)-2-methyl-propane-1,2-diamine

The title compound was obtained as a colorless oil, MS: m/e=292.0(M+H⁺), using chemistry similar to that described in Example 1, step 1from 2-fluoro-5-iodopyridine and 2-methylpropane-1,2-diamine.

Step 2: 1-(5-Iodo-pyridin-2-yl)-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=318.0(M+H⁺), using chemistry similar to that described in Example 1, step 2from N-1-(5-iodo-pyridin-2-yl)-2-methyl-propane-1,2-diamine (Example 15,step 1).

Step 3: 4,4-Dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=292.1 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example 15,step 2) and phenylacetylene.

Example 163,4,4-Trimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one

(110 mg, 378 μmol)4,4-Dimethyl-1-(5-(phenylethynyl)pyridin-2-yl)imidazolidin-2-one(Example 15, step 3) was dissolved in DMF (0.5 ml) and cooled to 0-5° C.NaH (55%) (19.8 mg, 453 μmol, 1.2 equiv.) was added and the mixture wasstirred for 30 min at 0-5° C. Iodomethane (35.3 μl, 566 μmol, 1.5equiv.) was added and the mixture was stirred for 30 min at 0-5° C. Thereaction mixture was treated with sat. NaHCO₃ solution and extractedtwice with a small volume of CH₂Cl₂. The organic layers were loadeddirectly to silica gel column and the crude material was purified byflash chromatography on silica gel (20 gr, ethyl acetate/heptanegradient, 0:100 to 100:0). The desired3,4,4-trimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one (93mg, 81% yield) was obtained as a yellow solid, MS: m/e=306.2 (M+H⁺).

Example 173-Ethyl-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a yellow oil, MS: m/e=320.2 (M+H⁺),using chemistry similar to that described in Example 16 starting from4,4-dimethyl-1-(5-(phenylethynyl)pyridin-2-yl)imidazolidin-2-one(Example 15, step 3) and iodoethane.

Example 183-Isopropyl-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a yellow oil, MS: m/e=334.3 (M+H⁺),using chemistry similar to that described in Example 16 starting from4,4-dimethyl-1-(5-(phenylethynyl)pyridin-2-yl)imidazolidin-2-one(Example 15, step 3) and 2-bromopropane.

Example 19(5RS)-5-tert-Butyl-5-methyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

Step 1: 1-Dibenzylamino-3,3-dimethyl-butan-2-one

(2.15 ml, 16.8 mmol) Dibenzylamine was dissolved in acetonitrile (30ml). Potassium carbonate (2.3 g, 16.8 mmol, 1.5 equiv.) and1-bromo-3,3-dimethylbutan-2-one (1.5 ml, 11.2 mmol, 1.0 equiv.) wereadded and the mixture was stirred for 16 hours at 90° C. The reactionmixture was extracted with sat. NaHCO₃-solution and two times EtOAc. Theorganic layers were extracted with water, dryed over Na₂SO₄, filteredand evaporated to dryness. The crude material was purified by flashchromatography on silica gel (70 gr, ethyl acetate/heptane gradient,0:100 to 100:0). The desired 1-(dibenzylamino)-3,3-dimethylbutan-2-one(1.6 g, 48.5% yield) was obtained as a yellow oil, MS: m/e=296.3 (M+H⁺).

Step 2: (RS)-1-Dibenzylamino-2,3,3-trimethyl-butan-2-ol

(1.6 g, 5.4 mmol) 1-Dibenzylamino-3,3-dimethyl-butan-2-one (Example 19,step 1) was dissolved in diethylether (20 ml) and cooled to 0-5° C.Methylmagnesium bromide (3M in diethylether) (2.2 ml, 6.5 mmol, 1.2equiv.) was added drop wise at 0-5° C. and the mixture was stirred for72 hours at room temperature. The reaction mixture was extracted withsat. NH₄Cl-solution and two times EtOAc. The organic layers wereextracted with water, dryed over Na₂SO₄, filtered and evaporated todryness. The crude material was purified by flash chromatography onsilica gel (50 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). Thedesired (RS)-1-dibenzylamino-2,3,3-trimethyl-butan-2-ol (1.2 g, 71%yield) was obtained as a yellow oil, MS: m/e=312.4 (M+H⁺).

Step 3: (RS)-1-Amino-2,3,3-trimethyl-butan-2-ol

The title compound was obtained as a white solid, MS: m/e=132.1 (M+H⁺),was prepared from (RS)-1-dibenzylamino-2,3,3-trimethyl-butan-2-ol(Example 19, step 2) by hydrogenation 16 hours at room temperature usingPd/C (10%) in ethyl acetate.

Step 4: (RS)-1-(5-Iodo-pyridin-2-ylamino)-2,3,3-trimethyl-butan-2-ol

The title compound was obtained as a yellow solid, MS: m/e=335.1 (M+H⁺),using chemistry similar to that described in Example 1, step 1 from2-fluoro-5-iodopyridine and (RS)-1-amino-2,3,3-trimethyl-butan-2-ol(Example 19, step 3).

Step 5:(5RS)-5-tert-Butyl-3-(5-iodo-pyridin-2-yl)-5-methyl-oxazolidin-2-one

The title compound was obtained as a yellow oil, MS: m/e=361.1 (M+H⁺),using chemistry similar to that described in Example 1, step 2 from(RS)-1-(5-iodo-pyridin-2-ylamino)-2,3,3-trimethyl-butan-2-ol (Example19, step 4).

Step 6:(5RS)-5-tert-Butyl-5-methyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=335.2(M+H⁺), using chemistry similar to that described in Example 1, step 3from(5RS)-5-tert-butyl-3-(5-iodo-pyridin-2-yl)-5-methyl-oxazolidin-2-one(Example 19, step 5) and phenylacetylene.

Example 205,5-Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

Step 1: 3-(5-Iodo-pyridin-2-yl)-5,5-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a colorless oil, MS: m/e=333.1(M+H⁺), using procedures similar to those described in Example 1, step 1and step 2 from 2-fluoro-5-iodopyridine and3-amino-2,2-dimethylpropan-1-ol.

Step 2:5,5-Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a light brown oil, MS: m/e=307.3(M+H⁺), using chemistry similar to that described in Example 1, step 3from 3-(5-iodo-pyridin-2-yl)-5,5-dimethyl-[1,3]oxazinan-2-one (Example20, step 1) and phenylacetylene.

Example 211-(3-Fluoro-5-phenylethynyl-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a orange solid, MS: m/e=309.2 (M+H⁺),using procedures similar to those described in Example 13 by using2-amino-3-fluoro-5-iodopyridine instead of 5-iodopyridin-2-amine.

Example 22 (3aRS,6aSR)-3-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one

Step 1:(3aRS,6aSR)-3-(5-Iodo-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one

The title compound was obtained as a light brown solid, MS: m/e=331.1(M+H⁺), using procedures similar to those described in Example 1, step 1and step 2 from 2-fluoro-5-iodopyridine and(1SR,2RS)-2-aminocyclopentanol hydrochloride.

Step 2:(3aRS,6aSR)-3-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one

The title compound was obtained as a light yellow solid, MS: m/e=305.2(M+H⁺), using chemistry similar to that described in Example 1, step 3from(3aRS,6aSR)-3-(5-iodo-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one(Example 13, step 1) and phenylacetylene.

Example 23 (3aRS,6aSR)-3-(5-Pyridin-3-ylethynyl-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one

The title compound was obtained as a colorless oil, MS: m/e=306.2(M+H⁺), using chemistry similar to that described in Example 1, step 3from(3aRS,6aSR)-3-(5-iodo-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one(Example 13, step 1) and 3-ethynyl-pyridine.

Example 24(3aRS,6aSR)-3-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-hexahydro-cyclopentaoxazol-2-one

The title compound was obtained as a light brown solid, MS: m/e=324.2(M+H⁺), using chemistry similar to that described in Example 1, step 3from(3aRS,6aSR)-3-(5-iodo-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one(Example 13, step 1) and 3-ethynyl-5-fluoro-pyridine (CAS 872122-54-8).

Example 255,5-Dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=306.2(M+H⁺), using procedures similar to those described in Example 15starting from 2-fluoro-5-iodopyridine and by using2,2-dimethylpropane-1,3-diamine instead of 2-methylpropane-1,2-diamine.

Example 261,5,5-Trimethyl-3-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=306.2(M+H⁺), using procedures similar to those described in Example 16 from5,5-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one(Example 25) and iodomethane.

Example 27(RS)-4,5,5-Trimethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=307.2 (M+H⁺),using procedures similar to those described in Example 1 from2-fluoro-5-iodopyridine and by using (RS)-3-amino-2-methyl-butan-2-ol(CAS 6291-17-4) instead of 1-amino-2-methylpropan-2-ol.

Example 284,4,5,5-Tetramethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=321.2(M+H⁺), using procedures similar to those described in Example 1 from2-fluoro-5-iodopyridine and by using 3-amino-2,3-dimethyl-butan-2-ol(CAS 89585-13-7) instead of 1-amino-2-methylpropan-2-ol.

Example 293-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one

Step 1:5,5-Dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a brown solid, MS: m/e=289.0 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from3-(5-iodo-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one (Example 5,step 1) and ethynyltrimethylsilane.

Step 2:3-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one

5,5-Dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-oxazolidin-2-one(Example 29, step 1) (100 mg, 0.35 mmol) was dissolved in THF (3 ml).3-Fluoro-5-iodopyridine (100 mg, 0.45 mmol, 1.3 equiv.), Et₃N (145 μl,1.04 mmol, 3 equiv.), Bis-(triphenylphosphine)-palladium(II)dichloride(10 mg, 14 μmol, 0.05 equiv.), triphenylphosphine (11 mg, 17 μmol, 0.05equiv.), triphenylphosphine (3 mg, 10 μmol, 0.03 equiv.) andcopper(I)iodide (1 mg, 3.5 μmol, 0.01 equiv.) were added under nitrogenand the mixture was heated to 60° C. TBAF 1M in THF (520 μl, 0.52 mmol,1.5 equiv.) was added dropwise in 20 minutes at 60° C. The reactionmixture was stirred for 3 hours at 60° C. Sat. NaHCO₃ solution was addedand the mixture was extracted with dichloromethane. The organic extractswere dried with sodium sulfate, filtered and evaporated. The crudeproduct was purified by flash chromatography on silica gel(dichloromethane/methanol gradient 100:0 to 90:10). The desired3-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-onewas obtained as a white solid (55 mg, 51% yield), MS: m/e=312.3 (M+H⁺).

Example 305,5-Dimethyl-3-(5-pyrimidin-5-ylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=295.2(M+H⁺), using chemistry similar to that described in Example 29, step 2from5,5-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-oxazolidin-2-one(Example 29, step 1) and 5-bromopyrimidine.

Example 315,5-Dimethyl-3-[5-(1-methyl-1H-pyrazol-4-ylethynyl)-pyridin-2-yl]-oxazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=297.2(M+H⁺), using chemistry similar to that described in Example 29, step 2from5,5-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-oxazolidin-2-one(Example 29, step 1) and 4-iodo-1-methyl-1H-pyrazole.

Example 323-[5-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=311.2 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from3-(5-iodo-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one (Example 5,step 1) and 1-ethynyl-4-fluoro-benzene.

Example 333-[5-(3,4-Difluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=329.2 (M+H⁺),using chemistry similar to that described in Example 29, step 2 from5,5-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-oxazolidin-2-one(Example 29, step 1) and 1,2-difluoro-4-iodobenzene.

Example 343-[5-(2,5-Difluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=329.2 (M+H⁺),using chemistry similar to that described in Example 29, step 2 from5,5-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-oxazolidin-2-one(Example 29, step 1) and 1,4-difluoro-2-iodobenzene.

Example 353-[5-(6-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=312.2 (M+H⁺),using chemistry similar to that described in Example 29, step 2 from5,5-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-oxazolidin-2-one(Example 29, step 1) and 2-fluoro-5-iodopyridine.

Example 366-(5-Pyridin-3-ylethynyl-pyridin-2-yl)-4-oxa-6-aza-spiro[2.4]heptan-5-one

The title compound was obtained as a white solid, MS: m/e=292.2 (M+H⁺),using procedures similar to those described in Example 1 starting from2-fluoro-5-bromopyridine, 1-aminomethyl-cyclopropanol (Russian J. Org.Chem. 2001, 37, 1238) and 3-ethynyl-pyridine.

Example 371-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

Step 1: 2-Bromo-5-trimethylsilanylethynyl-pyridine

2-Bromo-5-iodopyridine (2.5 g, 8.8 mmol) was dissolved under nitrogen in50 ml THF. Bis-(triphenylphosphine)-palladium(II)dichloride (618 mg, 880μmol, 0.1 equiv.), ethynyltrimethylsilane (950 mg, 1.34 ml, 9.6 mmol,1.1 equiv.), triethylamine (1.78 g, 2.44 ml, 17.6 mmol, 3 equiv.) andcopper(I)iodide (84 mg, 440 μmol, 0.05 equiv.) were added and themixture was stirred for 3 hours at 50° C. The reaction mixture wascooled and evaporated to dryness. The crude product was purified byflash chromatography on silica gel, eluting with an ethylacetate:heptane gradient 0:100 to 15:85. The desired2-bromo-5-trimethylsilanylethynyl-pyridine (1.95 g, 7.7 mmol, 87% yield)was obtained as a white solid, MS: m/e=254.1/256.1 (M+H⁺).

Step 2:4,4-Dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one

(260 mg, 1.0 mmol) 2-Bromo-5-trimethylsilanylethynyl-pyridine (Example37, step 1) was dissolved in toluene (2 ml) and4,4-dimethylpyrrolidin-2-one (115 mg, 1.0 mmol, 1.0 equiv.), cesiumcarbonate (660 mg, 2.05 mmol, 2.0 equiv.), xantphos (CAS 161265-03-8)(24 mg, 0.04 mmol, 0.04 equiv.) and Pd₂(dba)₃ (19 mg, 0.02 mmol, 0.02equiv.) were added under nitrogen. The mixture was stirred for 1 hour at90° C. The crude product was purified by flash chromatography bydirectly loading the toluene mixture onto a silica gel column andeluting with an ethyl acetate:heptane gradient 0:100 to 40:60. Thedesired4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one(230 mg, 0.81 mmol, 75% yield) was obtained as a yellow solid, MS:m/e=287.1 (M+H⁺).

Step 3:1-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

4,4-Dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one(Example 37, step 2) (80 mg, 0.28 mmol) was dissolved in DMF (1 ml).3-Fluoro-5-iodopyridine (87 mg, 0.39 mmol, 1.4 equiv.), Et₃N (85 mg, 117μl, 0.84 mmol, 3 equiv.),Bis-(triphenylphosphine)-palladium(II)dichloride (10 mg, 14 μmol, 0.05equiv.), triphenylphosphine (2 mg, 8.4 μmol, 0.03 equiv.) andcopper(I)iodide (2 mg, 8.4 μmol, 0.03 equiv.) were added under nitrogenand the mixture was heated to 70° C. TBAF 1M in THF (300 μl, 0.3 mmol,1.1 equiv.) was added dropwise in 20 minutes at 70° C. The reactionmixture was stirred for 30 minutes at 70° C. and evaporated with isoluteto dryness. The crude product was purified by flash chromatography witha 20 g silica gel column and eluting with heptane:ethyl acetate100:0->0:100. The desired1-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one(36 mg, 42% yield) was obtained as a white solid, MS: m/e=310.2 (M+H⁺).

Example 384,4-Dimethyl-1-(5-pyridin-3-ylethynyl-pyridin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a white solid, MS: m/e=292.1 (M+H⁺),using chemistry similar to that described in Example 37, step 3 from4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one(Example 37, step 2) and 3-iodopyridine.

Example 391-[5-(5-Chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a white solid, MS: m/e=326.2/328.2(M+H⁺), using chemistry similar to that described in Example 37, step 3from4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one(Example 37, step 2) and 3-chloro-5-iodopyridine.

Example 401-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a white solid, MS: m/e=309.2 (M+H⁺),using chemistry similar to that described in Example 37, step 3 from4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one(Example 37, step 2) and 1-fluoro-3-iodobenzene.

Example 414,4-Dimethyl-1-(3-methyl-5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

Step 1: 2-Bromo-3-methyl-5-trimethylsilanylethynyl-pyridine

The title compound was obtained as a yellow oil, MS: m/e=268.1/270.1(M+H⁺), using chemistry similar to that described in Example 37, step 1by using 2-bromo-5-iodo-3-methylpyridine instead of2-bromo-5-iodopyridine.

Step 2:4,4-Dimethyl-1-(3-methyl-5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a brown solid, MS: m/e=301.3 (M+H⁺),using chemistry similar to that described in Example 37, step 2 from2-bromo-3-methyl-5-trimethylsilanylethynyl-pyridine (Example 41, step 1)and 4,4-dimethylpyrrolidin-2-one.

Step 3:4,4-Dimethyl-1-(3-methyl-5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a white solid, MS: m/e=305.3 (M+H⁺),using chemistry similar to that described in Example 37, step 3 from4,4-dimethyl-1-(3-methyl-5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one(Example 41, step 2) and iodobenzene.

Example 425,5-Dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

Step 1:5,5-Dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a yellow solid, MS: m/e=301.3 (M+H⁺),using chemistry similar to that described in Example 37, step 2 from2-bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) and byusing 5,5-dimethyl-piperidin-2-one (CAS 4007-79-8) instead of4,4-dimethylpyrrolidin-2-one.

Step 2:5,5-Dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a yellow oil, MS: m/e=305.2 (M+H⁺),using chemistry similar to that described in Example 37, step 3 from5,5-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one(Example 42, step 1) and iodobenzene.

Example 435′-(3-Fluoro-phenylethynyl)-5,5-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a yellow oil, MS: m/e=323.2 (M+H⁺),using chemistry similar to that described in Example 37, step 3 from5,5-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one(Example 42, step 1) and 1-fluoro-3-iodobenzene.

Example 441-Methyl-3-(5-phenylethynyl-pyridin-2-yl)-1,3-diaza-spiro[4.4]nonan-2-one

Step 1: {1-[(5-Iodo-pyridin-2-ylamino)-methyl]-cyclopentyl}-carbamicacid tert-butyl ester

The title compound was obtained as a white solid, MS: m/e=418.2 (M+H⁺),using chemistry similar to that described in Example 1, step 1 from2-fluoro-5-iodopyridine and tert-butyl1-(aminomethyl)cyclopentylcarbamate (CAS 889949-09-1) by using neatpyridine as solvent instead of NMP.

Step 2: (1-Amino-cyclopentylmethyl)-(5-iodo-pyridin-2-yl)-aminehydrochloride

The BOC protecting group is removed by reacting{1-[(5-iodo-pyridin-2-ylamino)-methyl]-cyclopentyl}-carbamic acidtert-butyl ester (Example 44, step 1) with 4N HCl in dioxane for 1 hourat room temperature. The title compound was obtained by filtration ofthe hydrochloride salt as a light yellow solid, MS: m/e=318.1 (M+H⁺).

Step 3: 3-(5-Iodo-pyridin-2-yl)-1,3-diaza-spiro[4.4]nonan-2-one

The title compound was obtained as a white solid, MS: m/e=344.1 (M+H⁺),using chemistry similar to that described in Example 1, step 2 from(1-amino-cyclopentylmethyl)-(5-iodo-pyridin-2-yl)-amine hydrochloride(Example 44, step 2).

Step 4: 3-(5-Phenylethynyl-pyridin-2-yl)-1,3-diaza-spiro[4.4]nonan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=318.2(M+H⁺), using chemistry similar to that described in Example 1, step 3from 3-(5-iodo-pyridin-2-yl)-1,3-diaza-spiro[4.4]nonan-2-one (Example44, step 3) and phenylacetylene.

Step 5:1-Methyl-3-(5-phenylethynyl-pyridin-2-yl)-1,3-diaza-spiro[4.4]nonan-2-one

The title compound was obtained as a light yellow oil, MS: m/e=332.2(M+H⁺), using chemistry similar to that described in Example 16 from3-(5-phenylethynyl-pyridin-2-yl)-1,3-diaza-spiro[4.4]nonan-2-one(Example 44, step 4) and iodomethane.

Example 45(RS)-4-Cyclopentyl-3-methyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=346.2(M+H⁺), using procedures similar to those described in Example 44 from2-fluoro-5-iodopyridine and by using (RS)-tert-butyl2-amino-1-cyclopentylethylcarbamate (CAS 936497-76-6) instead oftert-butyl 1-(aminomethyl)cyclopentylcarbamate.

Example 46(1RS,5SR)-6-(5-Phenylethynyl-pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7-one

Step 1:(1RS,5SR)-6-(5-Bromo-pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7-one

The title compound was obtained as a white solid, MS: m/e=268.2 (M+H⁺),using chemistry similar to that described in Example 37, step 2 from2,5-dibromopyridine and (1RS,5SR)-6-aza-bicyclo[3.2.0]heptan-7-one (CAS22031-52-3).

Step 2:(1RS,5SR)-6-(5-Phenylethynyl-pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7-one

The title compound was obtained as a brown solid, MS: m/e=289.2 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from(1RS,5SR)-6-(5-bromo-pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7-one(Example 46, step 1) with phenylacetylene.

Example 47(6SR,7RS)-3-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-benzooxazol-2-one

The title compound was obtained as a yellow solid, MS: m/e=319.2 (M+H⁺),using procedures similar to those described in Example 1 starting from2-fluoro-5-bromopyridine, (5SR,6RS)-2-amino-cyclohexanol hydrochloride(CAS 190792-72-4) and phenylacetylene.

Example 483,4,4-Trimethyl-1-(5-pyridin-3-ylethynyl-pyridin-2-yl)-imidazolidin-2-one

Step 1: 1-(5-Iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=332.1(M+H⁺), using chemistry similar to that described in Example 16 from1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example 15,step 2) and iodomethane.

Step 2:3,4,4-Trimethyl-1-(5-pyridin-3-ylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=307.3 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from1-(5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 48,step 1) and 3-ethynyl-pyridine.

Example 491-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

Step 1:3,4,4-Trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=302.3 (M+H⁺),using chemistry similar to that described in Example 37, step 1 from1-(5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 48,step 1) and ethynyltrimethylsilane.

Step 2:1-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=325.4(M+H⁺), using chemistry similar to that described in Example 37, step 3from3,4,4-trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-imidazolidin-2-one(Example 49, step 1) and 3-fluoro-5-iodopyridine.

Example 503,4,4-Trimethyl-1-[5-(1-methyl-1H-pyrazol-4-ylethynyl)-pyridin-2-yl]-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=310.3(M+H⁺), using chemistry similar to that described in Example 37, step 3from3,4,4-trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-imidazolidin-2-one(Example 49, step 1) and 4-iodo-1-methyl-1H-pyrazole.

Example 511-[5-(5-Chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=341.1/343.3(M+H⁺), using chemistry similar to that described in Example 37, step 3from3,4,4-trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-imidazolidin-2-one(Example 49, step 1) and 3-chloro-5-iodopyridine.

Example 523,4,4-Trimethyl-1-(5-pyridazin-4-ylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=308.4(M+H⁺), using chemistry similar to that described in Example 37, step 3from3,4,4-trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-imidazolidin-2-one(Example 49, step 1) and 4-bromo-pyridazine.

Example 531-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=324.3 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from1-(5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 48,step 1) and 1-ethynyl-3-fluoro-benzene.

Example 541-[5-(3-Chloro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=340.1/342.2(M+H⁺), using chemistry similar to that described in Example 1, step 3from 1-(5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example48, step 1) and 1-ethynyl-3-chloro-benzene.

Example 553,4,4-Trimethyl-1-(5-pyrimidin-5-ylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=308.2(M+H⁺), using chemistry similar to that described in Example 37, step 3from3,4,4-trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-imidazolidin-2-one(Example 49, step 1) and 5-bromo-pyrimidine.

Example 563,4,4-Trimethyl-1-(5-m-tolylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a brown oil, MS: m/e=320.1 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from1-(5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 48,step 1) and 1-ethynyl-3-methyl-benzene.

Example 571-[5-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=324.2(M+H⁺), using chemistry similar to that described in Example 1, step 3from 1-(5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example48, step 1) and 1-ethynyl-4-fluoro-benzene.

Example 58(RS)-2-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one

Step 1:(RS)-2-(5-Iodo-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one

The title compound was obtained as a white solid, MS: m/e=344.0 (M+H⁺),using procedures similar to those described in Example 1, step 1 andstep 2 from 2-fluoro-5-iodopyridine and(RS)-hexahydro-imidazo[1,5-a]pyridin-3-one (CAS 76561-92-7) by usingneat pyridine as solvent instead of NMP.

Step 2:(RS)-2-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one

The title compound was obtained as a white solid, MS: m/e=318.2 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from(RS)-2-(5-iodo-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one(Example 58, step 1) and phenylacetylenen.

Example 59 2-(5-Phenylethynyl-pyridin-2-yl)-2-aza-spiro[4.4]nonan-3-one

The title compound was obtained as a light yellow, MS: m/e=317.2 (M+H⁺),using chemistry similar to that described in Example 37, step 2 from2-bromo-5-phenylethynyl-pyridine (Example 58, step 1) and2-aza-spiro[4.4]nonan-3-one (CAS 75751-72-3).

Example 60(RS)-3-Methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

Step 1:(RS)-4-Iodo-N-(5-iodo-pyridin-2-yl)-2-methoxy-3,3-dimethyl-butyramide

The title compound was obtained as a white solid, MS: m/e=474.9 (M+H⁺),using chemistry similar to that described in patent WO9637466, page 17,step 2 starting from (RS)-3-methoxy-4,4-dimethyl-dihydro-furan-2-one(CAS 100101-82-4) instead of 3-t-butylcarbamoyloxy-tetrahydrofuran-2-oneand by using 2-amino-5-iodopyridine instead of2-amino-4-trifluoromethylpyridine.

Step 2:(RS)-1-(5-Iodo-pyridin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=347.0(M+H⁺), using chemistry similar to that described in patent WO9637466,page 17, step 3 from(RS)-4-iodo-N-(5-iodo-pyridin-2-yl)-2-methoxy-3,3-dimethyl-butyramide(Example 60, step 1).

Step 3:(RS)-3-Methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=321.3(M+H⁺), using chemistry similar to that described in Example 1, step 3from(RS)-1-(5-iodo-pyridin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one(Example 60, step 2) and phenylacetylene.

Example 61 (5R or5S)-5-Methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound, a yellow oil, MS: m/e=321.3 (M+H⁺), was prepared byseparation of(RS)-3-methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one(Example 60) using a chiral column (chiralpak AD withheptane:isopropanol 90:10 as solvent).

Example 62 (5S or5R)-5-Methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound, a white solid, MS: m/e=321.3 (M+H⁺), was prepared byseparation of(RS)-3-methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one(Example 60) using a chiral column (chiralpak AD withheptane:isopropanol 90:10 as solvent).

Example 63(RS)-1-[5-(5-Chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

Step 1:(RS)-3-Methoxy-4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=317.2 (M+H⁺),using chemistry similar to that described in Example 37, step 1 from(RS)-1-(5-iodo-pyridin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one(Example 60, step 2) and ethynyltrimethylsilane.

Step 2:(RS)-1-[5-(5-Chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a white solid, MS: m/e=356.1/358.2(M+H⁺), using chemistry similar to that described in Example 37, step 3from(RS)-3-methoxy-4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one(Example 63, step 1) and 3-chloro-5-iodopyridine.

Example 64(RS)-3-Methoxy-4,4-dimethyl-1-(5-m-tolylethynyl-pyridin-2-yl)-pyrrolidin-2-one

The title compound was obtained as an orange oil, MS: m/e=335.2 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from(RS)-1-(5-iodo-pyridin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one(Example 60, step 2) and 1-ethynyl-3-methyl-benzene.

Example 65(RS)-1-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a brown solid, MS: m/e=339.2 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from(RS)-1-(5-iodo-pyridin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one(Example 60, step 2) and 1-ethynyl-3-fluorobenzene.

Example 66(RS)-1-[5-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a brown solid, MS: m/e=339.2 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from(RS)-1-(5-iodo-pyridin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one(Example 60, step 2) and 1-ethynyl-4-fluorobenzene.

Example 673,4,4-Trimethyl-1-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one

Step 1: [3-(5-Iodo-pyridin-2-ylamino)-1,1-dimethyl-propyl]-carbamic acidtert-butyl ester

The title compound was obtained as a white solid, MS: m/e=406.3 (M+H⁺),using chemistry similar to that described in Example 1, step 1 from2-fluoro-5-iodopyridine and tert-butyl4-amino-2-methylbutan-2-ylcarbamate (CAS 880100-43-6).

Step 2: N-1-(5-Iodo-pyridin-2-yl)-3-methyl-butane-1,3-diaminehydrochloride

The BOC protecting group is removed byreacting[3-(5-iodo-pyridin-2-ylamino)-1,1-dimethyl-propyl]-carbamic acidtert-butyl ester (Example 67, step 1) with 4N HCl in dioxane for 4 hoursat room temperature. The title compound was obtained by filtration ofthe hydrochloride salt as a pink solid, MS: m/e=306.1 (M+H⁺).

Step 3: 1-(5-Iodo-pyridin-2-yl)-4,4-dimethyl-tetrahydro-pyrimidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=332.1 (M+H⁺),using chemistry similar to that described in Example 1, step 2 fromN-1-(5-iodo-pyridin-2-yl)-3-methyl-butane-1,3-diamine hydrochloride(Example 67, step 2).

Step 4:1-(5-Iodo-pyridin-2-yl)-3,4,4-trimethyl-tetrahydro-pyrimidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=346.0 (M+H⁺),using chemistry similar to that described in Example 16 from1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-tetrahydro-pyrimidin-2-one (Example67, step 3) and iodomethane.

Step 5:3,4,4-Trimethyl-1-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one

The title compound was obtained as a brown solid, MS: m/e=320.2 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from1-(5-iodo-pyridin-2-yl)-3,4,4-trimethyl-tetrahydro-pyrimidin-2-one(Example 67, step 4) and phenylacetylene.

Example 681-[5-(2,5-Difluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-tetrahydro-pyrimidin-2-one

Step 1:3,4,4-Trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one

The title compound was obtained as a white solid, MS: m/e=316.2 (M+H⁺),using chemistry similar to that described in Example 37, step 1 from1-(5-iodo-pyridin-2-yl)-3,4,4-trimethyl-tetrahydro-pyrimidin-2-one(Example 67, step 4) and ethynyltrimethylsilane.

Step 2:1-[5-(2,5-Difluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-tetrahydro-pyrimidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=356.2(M+H⁺), using chemistry similar to that described in Example 37, step 3from3,4,4-trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one(Example 68, step 1) and 1,4-difluoro-2-iodobenzene.

Example 691-[5-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-tetrahydro-pyrimidin-2-one

The title compound was obtained as a white solid, MS: m/e=338.3 (M+H⁺),using chemistry similar to that described in Example 37, step 3 from3,4,4-trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one(Example 68, step 1) and 1-fluoro-4-iodobenzene.

Example 70(RS)-2-(5-Pyridin-3-ylethynyl-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one

The title compound was obtained as a light yellow solid, MS: m/e=319.1(M+H⁺), using chemistry similar to that described in Example 1, step 3from (RS)-2-(5-iodo-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one(Example 58, step 1) and 3-ethynyl-pyridine.

Example 71(RS)-2-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-hexahydro-imidazo[1,5-a]pyridin-3-one

The title compound was obtained as a light brown solid, MS: m/e=336.2(M+H⁺), using chemistry similar to that described in Example 1, step 3from (RS)-2-(5-iodo-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one(Example 58, step 1) and 1-ethynyl-3-fluorobenzene.

Example 726,6-Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

Step 1: (3-Hydroxy-3-methyl-butyl)-carbamic acid benzyl ester

(10 g, 42.1 mmol) Methyl 3-(benzyloxycarbonylamino)propanoate (CAS54755-77-0) was dissolved in THF (150 ml) and cooled to 0-5° C. 3NMethylmagnesium bromide in THF (56.2 ml, 120 mmol, 4 equiv.) was addeddrop wise and the mixture stirred for 1 hour at 0-5° C. The reactionmixture was extracted with saturated NH₄Cl solution and two times withEtOAc. The organic layers were dried over Na₂SO₄ and evaporated todryness. The desired (3-hydroxy-3-methyl-butyl)-carbamic acid benzylester (11.6 g, quant.) was obtained as a colorless oil, MS: m/e=238.1(M+H⁺) and used in the next step without further purification.

Step 2: 6,6-dimethyl-[1,3]oxazinan-2-one

(11.6 g, 48.9 mmol) (3-Hydroxy-3-methyl-butyl)-carbamic acid benzylester (Example 72, step 1) was dissolved in THF (250 ml) and sodiumhydride (60%, 5.2 g, 108 mmol, 2.2 equiv.) was added in portions. Themixture was stirred for 3 hours at room temperature. 5 ml saturatedNaHCO₃ solution was added carefully and the mixture was evaporated withisolute to dryness. The crude product was purified by flashchromatography by directly loading the residue onto a silica gel columnand eluting with an ethyl acetate:methanol gradient 100:0 to 90:10. Thedesired 6,6-dimethyl-[1,3]oxazinan-2-one (3.2 g, 51% yield) was obtainedas a yellow solid, MS: m/e=130.1 (M+H⁺).

Step 3:6,6-Dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as an orange solid, MS: m/e=303.2(M+H⁺), using chemistry similar to that described in Example 37, step 2from 2-bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) andby using 6,6-dimethyl-[1,3]oxazinan-2-one (Example 72, step 2) insteadof 4,4-dimethylpyrrolidin-2-one.

Step 4:6,6-Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a yellow solid, MS: m/e=307.2 (M+H⁺),using chemistry similar to that described in Example 37, step 3 from6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one(Example 72, step 3) and iodobenzene.

Example 736,6-Dimethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

Step 1: 3-(5-Iodo-pyridin-2-yl)-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a white solid, MS: m/e=333.1 (M+H⁺),using procedures similar to those described in Example 1, step 1 andstep 2 from 2-fluoro-5-iodopyridine and 4-amino-2-methyl-butan-2-olhydrochloride.

Step 2:6,6-Dimethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=308.2(M+H⁺), using chemistry similar to that described in Example 1, step 3from 3-(5-iodo-pyridin-2-yl)-6,6-dimethyl-[1,3]oxazinan-2-one (Example73, step 1) and phenylacetylene.

Example 743-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a white solid, MS: m/e=326.3 (M+H⁺),using chemistry similar to that described in Example 37, step 3 from6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one(Example 72, step 3) and 3-fluoro-5-iodopyridine.

Example 753-[5-(5-Chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a white solid, MS: m/e=342.1/344.2(M+H⁺), using chemistry similar to that described in Example 37, step 3from6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one(Example 72, step 3) and 3-chloro-5-iodopyridine.

Example 763-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a white solid, MS: m/e=325.4 (M+H⁺),using chemistry similar to that described in Example 37, step 3 from6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one(Example 72, step 3) and 1-fluoro-3-iodobenzene.

Example 773-[5-(3-Chloro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a white solid, MS: m/e=341.2/343.2(M+H⁺), using chemistry similar to that described in Example 37, step 3from6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one(Example 72, step 3) and 1-chloro-3-iodobenzene.

Example 786,6-Dimethyl-3-(5-m-tolylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=321.4(M+H⁺), using chemistry similar to that described in Example 37, step 3from6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one(Example 72, step 3) and 1-iodo-3-methylbenzene.

Example 793-[5-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a light brown solid, MS: m/e=325.2(M+H⁺), using chemistry similar to that described in Example 1, step 3from 3-(5-iodo-pyridin-2-yl)-6,6-dimethyl-[1,3]oxazinan-2-one (Example73, step 1) and 1-ethynyl-4-fluorobenzene.

Example 803-[5-(3,4-Difluoro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=343.1(M+H⁺), using chemistry similar to that described in Example 1, step 3from 3-(5-iodo-pyridin-2-yl)-6,6-dimethyl-[1,3]oxazinan-2-one (Example73, step 1) and 4-ethynyl-1,2-difluorobenzene.

Example 813-[5-(2,5-Difluoro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=343.1(M+H⁺), using chemistry similar to that described in Example 37, step 3from6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one(Example 72, step 3) and 1,4-difluoro-2-iodobenzene.

Example 826-(5-Phenylethynyl-pyridin-2-yl)-2-oxa-6-aza-spiro[3.4]octan-7-one

Step 1:6-(5-Trimethylsilanylethynyl-pyridin-2-yl)-2-oxa-6-aza-spiro[3.4]octan-7-one

The title compound was obtained as a white solid, MS: m/e=301.3 (M+H⁺),using chemistry similar to that described in Example 37, step 2 from2-bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) and2-oxa-6-aza-spiro[3.4]octan-7-one (CAS 1207174-87-5).

Step 2:6-(5-Phenylethynyl-pyridin-2-yl)-2-oxa-6-aza-spiro[3.4]octan-7-one

The title compound was obtained as a light yellow solid, MS: m/e=305.3(M+H⁺), using chemistry similar to that described in Example 37, step 3from6-(5-trimethylsilanylethynyl-pyridin-2-yl)-2-oxa-6-aza-spiro[3.4]octan-7-one(Example 82, step 1) and iodobenzene.

Example 83(RS)-4-Cyclopropyl-3-methyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as an orange solid, MS: m/e=318.1(M+H⁺), using procedures similar to those described in Example 58 from2-fluoro-5-iodopyridine and by using(RS)-1-cyclopropyl-ethane-1,2-diamine instead of(RS)-hexahydro-imidazo[1,5-a]pyridin-3-one.

Example 84 (3aSR,7aRS)-(3aRS,7RS)-1-Methyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one

Step 1:(1SR,2RS)-(1RS,2RS)—N-(5-Iodo-pyridin-2-yl)-cyclohexane-1,2-diamine

The title compound was obtained as a brown oil, MS: m/e=318.1 (M+H⁺),using chemistry similar to that described in Example 1, step 1 from2-fluoro-5-iodopyridine and rac-cyclohexane-1,2-diamine.

Step 2:(3aSR,7aRS)-(3aRS,7aRS)-1-(5-Iodo-pyridin-2-yl)-octahydro-benzoimidazol-2-one

The title compound was obtained as a yellow solid, MS: m/e=344.1 (M+H⁺),using chemistry similar to that described in Example 1, step 2 from(1SR,2RS)-(1RS,2RS)—N-(5-iodo-pyridin-2-yl)-cyclohexane-1,2-diamine(Example 84, step 1).

Step 3:(3aSR,7aRS)-(3aRS,7aRS)-1-(5-Iodo-pyridin-2-yl)-3-methyl-octahydro-benzoimidazol-2-one

The title compound was obtained as a white solid, MS: m/e=358.0 (M+H⁺),using chemistry similar to that described in Example 16 from(3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-octahydro-benzoimidazol-2-one(Example 84, step 2) and iodomethane.

Step 4:(3aSR,7aRS)-(3aRS,7RS)-1-Methyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one

The title compound was obtained as a yellow solid, MS: m/e=332.3 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from(3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-3-methyl-octahydro-benzoimidazol-2-one(Example 84, step 3) and phenylacetylene.

Example 85(3aSR,7aRS)-(3aRS,7RS)-1-Methyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one

The title compound was obtained as a light yellow solid, MS: m/e=333.3(M+H⁺), using chemistry similar to that described in Example 1, step 3from(3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-3-methyl-octahydro-benzoimidazol-2-one(Example 84, step 3) and 3-ethynylpyridine.

Example 86(3aSR,7aRS)-(3aRS,7RS)-1-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-3-methyl-octahydro-benzoimidazol-2-one

The title compound was obtained as a light yellow solid, MS: m/e=351.3(M+H⁺), using chemistry similar to that described in Example 1, step 3from(3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-3-methyl-octahydro-benzoimidazol-2-one(Example 84, step 3) and 3-ethynyl-5-fluoro-pyridine (generated by insitu Sonogashira reaction of 3-fluoro-5-iodopyridine withethynyltrimethylsilane and TBAF).

Example 874,4-Dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

Step 1:4,4-Dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a yellow solid, MS: m/e=301.3 (M+H⁺),using chemistry similar to that described in Example 37, step 2 from2-bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) and byusing 4,4-dimethyl-piperidin-2-one (CAS 55047-81-9) instead of4,4-dimethylpyrrolidin-2-one.

Step 2:4,4-Dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a white solid, MS: m/e=305.2 (M+H⁺),using chemistry similar to that described in Example 37, step 3 from4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one(Example 87, step 1) and iodobenzene.

Example 885′-(3-Fluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a white solid, MS: m/e=323.2 (M+H⁺),using chemistry similar to that described in Example 37, step 3 from4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one(Example 87, step 1) and 1-fluoro-3-iodobenzene.

Example 895′-(3-Chloro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a light yellow solid, MS:m/e=339.2/341.1 (M+H⁺), using chemistry similar to that described inExample 37, step 3 from4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one(Example 87, step 1) and 1-chloro-3-iodobenzene.

Example 905′-(5-Chloro-pyridin-3-ylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a light yellow solid, MS:m/e=340.1/342.2 (M+H⁺), using chemistry similar to that described inExample 37, step 3 from4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one(Example 87, step 1) and 1-chloro-3-iodopyridine.

Example 915′-(4-Fluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a light yellow solid, MS: m/e=323.2(M+H⁺), using chemistry similar to that described in Example 37, step 3from4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one(Example 87, step 1) and 1-fluoro-4-iodobenzene.

Example 925′-(2,5-Difluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a white solid, MS: m/e=341.1 (M+H⁺),using chemistry similar to that described in Example 37, step 3 from4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one(Example 87, step 1) and 1,4-difluoro-2-iodobenzene.

Example 937,7-Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazepan-2-one

Step 1: 3-(5-Iodo-pyridin-2-yl)-7,7-dimethyl-[1,3]oxazepan-2-one

The title compound was obtained as a colorless oil, MS: m/e=346.9(M+H⁺), using procedures similar to those described in Example 1, step 1and step 2 from 2-fluoro-5-iodopyridine and 5-amino-2-methylpentan-2-ol(CAS 108262-66-4).

Step 2:7,7-Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazepan-2-one

The title compound was obtained as an orange solid, MS: m/e=321.2(M+H⁺), using chemistry similar to that described in Example 1, step 3from 3-(5-iodo-pyridin-2-yl)-7,7-dimethyl-[1,3]oxazepan-2-one (Example93, step 1) and phenylacetylene.

Example 94 (3aSR,7aRS)-(3aRS,7RS)-1-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-pyrano[4,3-d]oxazol-2-one

Step 1:(3aSR,7aRS)-(3aRS,7RS)-1-(5-Iodo-pyridin-2-yl)-hexahydro-pyrano[4,3-d]oxazol-2-one

The title compound was obtained as a white solid, MS: m/e=346.9 (M+H⁺),using procedures similar to those described in Example 1, step 1 andstep 2 from 2-fluoro-5-iodopyridine and(3RS,4RS)-(3RS,4SR)-4-aminotetrahydro-2H-pyran-3-ol (CAS 33332-01-3).

Step 2:(3aSR,7aRS)-(3aRS,7RS)-1-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-pyrano[4,3-d]oxazol-2-one

The title compound was obtained as a brown solid, MS: m/e=321.1 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from(3aSR,7aRS)-(3aRS,7RS)-1-(5-iodo-pyridin-2-yl)-hexahydro-pyrano[4,3-d]oxazol-2-one(Example 94, step 1) and phenylacetylene.

Example 95(RS)-5-Hydroxy-6,6-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

Step 1:(RS)-2-(tert-Butyl-diphenyl-silanyloxy)-3-dibenzylamino-propionic acidethyl ester

(5.8 g, 18.6 mmol) (RS)-3-Dibenzylamino-2-hydroxy-propionic acid ethylester (CAS 93715-75-4) was dissolved in DMF (40 ml) andtert-butylchlorodiphenylsilane (6.76 ml, 26 mmol, 1.4 equiv.), Imidazole(1.9 g, 27.9 mmol, 1.5 equiv.) and DMAP (227 mg, 1.9 mmol, 0.1 equiv.)were added at room temperature. The mixture was stirred for 3 hours at80° C. The reaction mixture was evaporated and extracted with saturatedNaHCO₃ solution and two times with EtOAc. The organic layers wereextracted with brine, dried over Na₂SO₄ and evaporated to dryness. Thecrude product was purified by flash chromatography on silica gel columnand eluting with an ethyl acetate:heptane gradient 0:100 to 40:60. Thedesired(RS)-2-(tert-butyl-diphenyl-silanyloxy)-3-dibenzylamino-propionic acidethyl ester (8.1 g, 79% yield) was obtained as a colorless oil, MS:m/e=552.5 (M+H⁺).

Step 2:(RS)-3-(tert-Butyl-diphenyl-silanyloxy)-4-dibenzylamino-2-methyl-butan-2-ol

(8.0 g, 14.5 mmol)(RS)-2-(tert-Butyl-diphenyl-silanyloxy)-3-dibenzylamino-propionic acidethyl ester (Example 95, step 1) was dissolved in THF (100 ml) andmethylmagnesium bromide (3M in diethylether) (19.3 ml, 58 mmol, 4equiv.) was drop wise at room temperature. The mixture was stirred for3.5 hours at room temperature. The reaction mixture was extracted withsaturated NaHCO₃ solution and two times with EtOAc. The organic layerswere extracted with brine, dried over Na₂SO₄ and evaporated to dryness.The desired(RS)-3-(tert-butyl-diphenyl-silanyloxy)-4-dibenzylamino-2-methyl-butan-2-ol(6.9 g, 84% yield) was obtained as a white solid, MS: m/e=538.5 (M+H⁺)and used in the next step without further purification.

Step 3:(RS)-4-Amino-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-butan-2-ol

(RS)-3-(tert-Butyl-diphenyl-silanyloxy)-4-dibenzylamino-2-methyl-butan-2-ol(Example 95, step 2) was hydrogenated in EtOH with Pd(OH)₂ for 16 hoursat 60° C. The desired(RS)-4-amino-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-butan-2-ol (4.2g, 92% yield) was obtained as a colorless oil, MS: m/e=358.2 (M+H⁺) andused in the next step without further purification.

Step 4:(RS)-5-(2,2-Dimethyl-1,1-diphenyl-propoxy)-6,6-dimethyl-[1,3]oxazinan-2-one

(1.83 mg, 5.1 mmol)(RS)-4-Amino-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-butan-2-ol(Example 95, step 3) was dissolved in THF (35 ml) and cooled to 0-5° C.Triethylamine (2.14 ml, 15.4 mmol, 3 equiv.) and triphosgene (1.67 g,5.63 mmol, 1.1 equiv.) dissolved in 15 ml THF were added drop wise at0-5° C. The mixture was stirred for 1 hour at 0-5° C. The reactionmixture was evaporated with isolute and the crude product was purifiedby flash chromatography by directly loading the residue onto a silicagel column and eluting with a heptane:ethyl acetate gradient 100:0 to0:100. The desired(RS)-5-(2,2-dimethyl-1,1-diphenyl-propoxy)-6,6-dimethyl-[1,3]oxazinan-2-one(535 mg, 27% yield) was obtained as a white solid, MS: m/e=384.3 (M+H⁺).

Step 5:(RS)-5-(2,2-Dimethyl-1,1-diphenyl-propoxy)-6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a yellow oil, MS: m/e=557.3 (M+H⁺),using chemistry similar to that described in Example 37, step 2 from2-bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) and(RS)-5-(2,2-dimethyl-1,1-diphenyl-propoxy)-6,6-dimethyl-[1,3]oxazinan-2-one(Example 95, step 4).

Step 6:(RS)-5-Hydroxy-6,6-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=323.1(M+H⁺), using chemistry similar to that described in Example 37, step 3from(RS)-5-(2,2-dimethyl-1,1-diphenyl-propoxy)-6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one(Example 95, step 5) and iodobenzene.

Example 964-Methyl-6-(5-phenylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one

Step 1: 2-Bromo-5-phenylethynyl-pyridine

The title compound was obtained as a white solid, MS: m/e=258/260(M+H⁺), using chemistry similar to that described in Example 37, step 1from 2-bromo-5-iodopyridine and by using phenylacetylene instead ofethynyltrimethylsilane.

Step 2: 4,6-Diaza-spiro[2.4]heptan-5-one

(0.88 g, 5.53 mmol) 1-(Aminomethyl)cyclopropanamine dihydrochloride (CAS849149-67-3) was dissolved in THF (10 ml) and CDI (0.9 g, 5.53 mmol, 1.0equiv.) was added at room temperature. The mixture was stirred for 16hours at 70° C. The reaction mixture was evaporated and extracted withsaturated NaHCO₃ solution and five times with dichloromethane. Theorganic layers were dried over Na₂SO₄ and evaporated to dryness. Thedesired 4,6-diaza-spiro[2.4]heptan-5-one (0.52 g, 50% purity, 42% yield)was obtained as a white solid, MS: m/e=113.0 (M+H⁺) and was used withoutfurther purification in the next step.

Step 3:6-(5-Phenylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one

The title compound was obtained as a yellow solid, MS: m/e=290.1 (M+H⁺),using chemistry similar to that described in Example 37, step 2 from2-bromo-5-phenylethynyl-pyridine (Example 96, step 1) and4,6-diaza-spiro[2.4]heptan-5-one (Example 96, step 2).

Step 4:4-Methyl-6-(5-phenylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one

The title compound was obtained as a white solid, MS: m/e=304.1 (M+H⁺),using chemistry similar to that described in Example 16 from6-(5-phenylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one(Example 96, step 3) and iodomethane.

Example 97 3,3-Dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-azetidin-2-one

Step 1: N-(5-Bromo-pyridin-2-yl)-3-chloro-2,2-dimethyl-propionamide

To a solution of 2-amino-5-bromopyridine (100 mg, 0.454 mmol) indichloromethane (6 ml) were added triethylamine (0.19 ml, 1.364 mmol, 3equiv.) and 3-chloro-2,2-dimethyl-propionyl chloride (CAS 4300-97-4)(140 mg, 0.909 mmol, 2 equiv.) at 0-5° C. The mixture was stirred for 16hours at room temperature. The reaction mixture was evaporated and thecrude product was purified by flash chromatography on silica gel columnand eluting with an ethyl acetate:heptane gradient 5:95 to 10:90. Thedesired N-(5-bromo-pyridin-2-yl)-3-chloro-2,2-dimethyl-propionamide (154mg, 74% yield) was obtained as a white solid.

Step 2: 1-(5-Bromo-pyridin-2-yl)-3,3-dimethyl-azetidin-2-one

(250 mg, 0.738 mmol)N-(5-Bromo-pyridin-2-yl)-3-chloro-2,2-dimethyl-propionamide (Example 97,step 1) dissolved in DMF (3 ml) was added at room temperature to asolution of NaH (29.5 mg, 0.738 mmol, 1 equiv.) in 5 ml DMF. The mixturewas stirred for 3 hours at 70° C. The reaction mixture was evaporatedand the crude product was purified by flash chromatography on silica gelcolumn and eluting with an ethyl acetate:heptane gradient 10:90 to15:85. The desired 1-(5-bromo-pyridin-2-yl)-3,3-dimethyl-azetidin-2-one(160 mg, 72% yield) was obtained as a white solid.

Step 3: 3,3-Dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-azetidin-2-one

The title compound was obtained as a brown solid, MS: m/e=277.0 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from1-(5-bromo-pyridin-2-yl)-3,3-dimethyl-azetidin-2-one (Example 97, step2) and phenylacetylene.

Example 98(1RS,5SR)-6-(5-Pyridin-3-ylethynyl-pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7-one

The title compound was obtained as a brown solid, MS: m/e=290.2 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from(1RS,5SR)-6-(5-bromo-pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7-one(Example 46, step 1) with 3-ethynyl-pyridine.

Example 99(3aSR,7aRS)-(3aRS,7RS)-1-Ethyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one

Step 1:(3aSR,7aRS)-(3aRS,7aRS)-1-(5-Iodo-pyridin-2-yl)-3-ethyl-octahydro-benzoimidazol-2-one

The title compound was obtained as a light yellow solid, MS: m/e=372.2(M+H⁺), using chemistry similar to that described in Example 16 from(3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-octahydro-benzoimidazol-2-one(Example 84, step 2) and iodoethane by stirring the reaction at 60° C.instead of 0-5° C.

Step 2:(3aSR,7aRS)-(3aRS,7RS)-1-Ethyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one

The title compound was obtained as a brown oil, MS: m/e=346.4 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from(3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-3-ethyl-octahydro-benzoimidazol-2-one(Example 99, step 1) and phenylacetylene.

Example 100 (3aSR,7aRS)-(3aRS,7RS)-1-Ethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one

The title compound was obtained as a brown solid, MS: m/e=347.8 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from(3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-3-ethyl-octahydro-benzoimidazol-2-one(Example 99, step 1) and 3-ethynyl-pyridine.

Example 101(3aSR,7aRS)-(3aRS,7RS)-1-Isopropyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one

Step 1:(3aSR,7aRS)-(3aRS,7aRS)-1-(5-Iodo-pyridin-2-yl)-3-isopropyl-octahydro-benzoimidazol-2-one

The title compound was obtained as a white solid using chemistry similarto that described in Example 16 from(3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-octahydro-benzoimidazol-2-one(Example 84, step 2) and isopropyl iodide by stirring the reaction at60° C. instead of 0-5° C.

Step 2:(3aSR,7aRS)-(3aRS,7RS)-1-Isopropyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one

The title compound was obtained as a brown oil, MS: m/e=360.1 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from(3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-3-isopropyl-octahydro-benzoimidazol-2-one(Example 101, step 1) and phenylacetylene.

Example 102(4aRS,7aSR)-3-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one

Step 1:(4aRS,7aSR)-3-(5-Iodo-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one

The title compound was obtained as a white solid, MS: m/e=345.0 (M+H⁺),using procedures similar to those described in Example 1, step 1 andstep 2 from 2-fluoro-5-iodopyridine and(1SR,2RS)-2-aminomethyl-cyclopentanol (CAS 40482-02-8) by usingtriphosgene and triethylamine in THF for 12 hours at room temperatureinstead of the conditions used in Example 1, step 2.

Step 2:(4aRS,7aSR)-3-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one

The title compound was obtained as a brown solid, MS: m/e=319.0 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from(4aRS,7aSR)-3-(5-iodo-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one(Example 102, step 1) and phenylacetylene.

Example 103(4aRS,7aRS)-3-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one

Step 1:(4aRS,7aRS)-3-(5-Iodo-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one

The title compound was obtained as a white solid, MS: m/e=345.0 (M+H⁺),using procedures similar to those described in Example 1, step 1 andstep 2 from 2-fluoro-5-iodopyridine and(1SR,2SR)-2-aminomethyl-cyclopentanol (CAS 40482-00-6) by usingtriphosgene and triethylamine in THF for 12 hours at room temperatureinstead of the conditions used in Example 1, step 2.

Step 2:(4aRS,7aRS)-3-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one

The title compound was obtained as a brown solid, MS: m/e=318.8 (M+H⁺),using chemistry similar to that described in Example 1, step 3 from(4aRS,7aRS)-3-(5-iodo-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one(Example 103, step 1) and phenylacetylene.

Example 104(RS)-5,6,6-Trimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

Step 1: (RS)-(3-Hydroxy-2,3-dimethyl-butyl)-carbamic acid tert-butylester

The title compound was obtained as a colorless oil, MS: m/e=218.3(M+H⁺), using chemistry similar to that described in Example 95, step 2from methyl 3-(tert-butoxycarbonylamino)-2-methylpropanoate (CAS182486-16-4).

Step 2: (RS)-5,6,6-Trimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a yellow solid, MS: m/e=144.0 (M+H⁺),using chemistry similar to that described in Example 72, step 2 from(RS)-(3-hydroxy-2,3-dimethyl-butyl)-carbamic acid tert-butyl ester(Example 104, step 1).

Step 3:(RS)-5,6,6-Trimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a yellow oil, MS: m/e=321.1 (M+H⁺),using chemistry similar to that described in Example 37, step 2 from2-bromo-5-phenylethynyl-pyridine (Example 96, step 1) and(RS)-5,6,6-trimethyl-[1,3]oxazinan-2-one (Example 104, step 2).

Example 105(RS)-6-Methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=323.1(M+H⁺), using chemistry similar to that described in Example 37, step 2from 2-bromo-5-phenylethynyl-pyridine (Example 96, step 1) and(RS)-6-methoxymethyl-[1,3]oxazinan-2-one (CAS 39754-63-7).

Example 106(3aRS,6aSR)-1-methyl-3-(5-(phenylethynyl)pyridin-2-yl)hexahydrocyclopenta[d]imidazol-2(1H)-one

Step 1: (3aSR, 6aRS)-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylicacid tert-butyl ester

A solution of(rac)-cis-2-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (2.28g, 9.98 mmol) and N-methylmorpholine (1.1 g, 1.21 ml, 11.0 mmol, 1.1equiv.) in 28 ml of dichloroethane was stirred at r.t. for 10 min. Thendiphenylphosphoricacid azide (3.02 g, 2.37 ml, 11.0 mmol, 1.1 equiv.)was added dropwise at room temperature and the colorless solution wasstirred for 45 min at room temperature during which the solution turnedlight yellow. The solution was then warmed to 75° C. and stirredovernight and allowed to cool. After workup with dichloromethane/water,the combined organic phases were evaporated to dryness. The orange solidwas triturated with ethyl acetate and filtered to give 1.27 g of a whitesolid. The mother liquors were concentrated and the cristallizedmaterial was again filtered to yield an additional 0.55 g of product.One obtains a total yield of 1.82 g (81%) of the title compound as acrystalline white solid, MS: m/e=227.3 (M+H⁺).

Step 2: (3aSR,6aRS)-3-Methyl-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acidtert-butyl ester

To a solution of (3aSR,6aRS)-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butylester (Example 106, step 1) (1.82 g, 8.04 mmol) in 30 ml of DMF wasadded a 60% suspension of sodium hydride in mineral oil (386 mg, 9.65mmol, 1.2 equiv.). The suspension was stirred for 45 minutes at roomtemperature (gas evolution), then iodomethane (0.604 ml, 9.65 mmol, 1.2equiv.) was added and the mixture was stirred at room temperatureovernight. After concentration in vaccuo and workup with ethylacetate/water, 2.05 g of a yellow oil were obtained containingmineral-oil drops which was directly used in the next step withoutfurther characterisation.

Step 3: (3aRS,6aSR)-1-Methyl-hexahydro-cyclopentaimidazol-2-one

To a solution of(3aSR,6aRS)-3-methyl-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylicacid tert-butyl ester (Example 106, step 2) (1.99 g, 8.28 mmol) in 30 mlof dichloromethane was added trifluoroacetic acid (7.55 g, 5.1 ml, 66.3mmol, 8 equiv.) and the yellow solution was stirred at for 5 h at roomtemperature. The reaction mixture was quenched by addition of saturatedsodium bicarbonate solution and the pH of the aqueous phase was set to9. After workup with dichloromethane/water, the organic phases weredried, filtered and concentrated in vaccuo to yield 1.07 g of anoff-white solid, which was taken up in cold ethyl acetate and filteredto yield the title compound (822 mg, 71%) as a crystalline white solidwhich was directly used in the next step without furthercharacterisation.

Step 4:(3aRS,6aSR)-1-methyl-3-(5-(phenylethynyl)pyridin-2-yl)hexahydrocyclopenta[d]imidazol-2(1H)-one

To a suspension of 2-bromo-5-(phenylethynyl)pyridine (Example 96,step 1) (55.0 mg, 0.213 mmol),(3aR,6aS)-1-methylhexahydrocyclopenta[d]imidazol-2(1H)-one (Example 106,step 3) (35.8 mg, 0.256 mmol, 1.2 equiv.), 139 mg cesium carbonate (139mg, 0.426 mmol, 2 equiv.), and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (5 mg, 0.008mmol, 0.04 equiv.) in 1 ml of toluene was added under argon atmospheretris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃) (4 mg, 0.0046 mmol,0.02 equiv.). The mixture was stirred overnight at 70° C. The mixturewas directly loaded on a 20 g silicagel column and was eluted with aheptane to 33% ethylacetate in heptane gradient to yield the titlecompound (49 mg, 73%) as an amorphous light-yellow solid, MS: m/e=318.1(M+H+).

Example 107(RS)-4-tert-Butyl-3-methyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=334.1(M+H⁺), using procedures similar to those described in Example 106starting from(rac)-2-(tert-butoxycarbonylamino-methyl)-3,3-dimethyl-butyric acidinstead of (rac)-cis-2-(tert-butoxycarbonylamino)cyclopentanecarboxylicacid.

Examples 1081-[5-(3-Fluoro-phenylethynyl)-3-methyl-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

Step 1:4,4-Dimethyl-1-(3-methyl-5-trimethylsilanylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=302.1 (M+H⁺),using chemistry similar to that described in Example 37, step 2 from2-bromo-3-methyl-5-trimethylsilanylethynyl-pyridine (Example 41, step 1)and 4,4-dimethyl-imidazolidin-2-one (CAS 24572-33-6).

Step 2:1-[5-(3-Fluoro-phenylethynyl)-3-methyl-pyridin-2-yl]-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=324.4(M+H⁺), using chemistry similar to that described in Example 37, step 3from4,4-dimethyl-1-(3-methyl-5-trimethylsilanylethynyl-pyridin-2-yl)-imidazolidin-2-one(Example 108, step 1) and 1-fluoro-3-iodobenzene.

Step 3:1-[5-(3-Fluoro-phenylethynyl)-3-methyl-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=338.3(M+H⁺), using chemistry similar to that described in Example 16 from1-[5-(3-fluoro-phenylethynyl)-3-methyl-pyridin-2-yl]-4,4-dimethyl-imidazolidin-2-one(Example 108, step 2) and iodomethane.

Example 109(3aSR,6aRS)-1-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-3-methyl-hexahydro-cyclopenta-imidazol-2-one

Step 1:(3aRS,6aSR)-1-Methyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-hexahydro-cyclopenta-imidazol-2-one

The title compound, an off-white solid, MS: m/e=314.1 (M+H⁺), wasprepared in accordance with the general method of example 106, step 4starting from 2-bromo-5-((trimethylsilyl)ethynyl)-pyridine (Example 37,step 1) and (3aRS,6aSR)-1-methylhexahydrocyclopenta[d]imidazol-2(1H)-one(Example 106, step 3).

Step 2:(3aSR,6aRS)-1-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-3-methyl-hexahydro-cyclopenta-imidazol-2-one

The title compound, a light yellow oil, MS: m/e=336.2 (M+H⁺), wasprepared in accordance with the general method of Example 37, step 3starting from(3aRS,6aSR)-1-methyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-hexahydro-cyclopenta-imidazol-2-one(Example 109, step 1) and 1-fluoro-3-iodobenzene.

Example 1101-[3-Fluoro-5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

Step 1: 1-(3-Fluoro-5-iodo-pyridin-2-yl)-4,4-dimethyl-imidazolidin-2-one

2,3-Difluoro-5-iodopyridine (300 mg, 1.24 mmol) was dissolved in 2 mltoluene. (140 mg, 1.24 mmol, 1 equiv.) 4,4-Dimethylimidazolidin-2-one(CAS 24572-33-6) and cesium carbonate (650 mg, 1.99 mmol, 1.6 equiv.)were added and the mixture was heated to 100° C. for 4 hours. Thereaction mixture was loaded directly onto a silica gel column andpurified by flash chromatography eluting with an ethyl acetate:heptanegradient 0:100 to 100:0. The desired1-(3-fluoro-5-iodo-pyridin-2-yl)-4,4-dimethyl-imidazolidin-2-one (205mg, 49% yield) was obtained as a white solid, MS: m/e=336.1 (M+H⁺).

Step 2:1-(3-Fluoro-5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one

The title compound, a yellow oil, MS: m/e=350.0 (M+H⁺), was prepared inaccordance with the general method of Example 16 from1-(3-fluoro-5-iodo-pyridin-2-yl)-4,4-dimethyl-imidazolidin-2-one(Example 110, step 1) and iodomethane.

Step 3:1-[3-Fluoro-5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=342.1(M+H⁺), using chemistry similar to that described in Example 1, step 3from 1-(3-fluoro-5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one(Example 110, step 2) and 1-ethynyl-4-fluorobenzene.

Example 1111-[3-Fluoro-5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=342.1(M+H⁺), using chemistry similar to that described in Example 1, step 3from 1-(3-fluoro-5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one(Example 110, step 2) and 1-ethynyl-3-fluorobenzene.

Example 1126-[5-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-4-methyl-4,6-diaza-spiro[2.4]heptan-5-one

Step 1: 4-Methyl-4,6-diaza-spiro[2.4]heptan-5-one

The title compound was obtained as a white solid using proceduressimilar to those described in Example 106, step 1 to 3 starting from1-((tert-butoxycarbonylamino)methyl)cyclopropanecarboxylic acid insteadof (rac)-cis-2-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid.

Step 2:4-Methyl-6-(5-trimethylsilanylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one

The title compound was obtained as a white solid, MS: m/e=300.2 (M+H⁺),using chemistry similar to that described in Example 37, step 2 from2-bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) and4-methyl-4,6-diaza-spiro[2.4]heptan-5-one (Example 112, step 1).

Step 3:6-[5-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-4-methyl-4,6-diaza-spiro[2.4]heptan-5-one

The title compound was obtained as a light yellow solid, MS: m/e=322.2(M+H⁺), using chemistry similar to that described in Example 37, step 3from4-methyl-6-(5-trimethylsilanylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one(Example 112, step 2) and 1-fluoro-4-iodobenzene.

Example 1136-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-4-methyl-4,6-diaza-spiro[2.4]heptan-5-one

The title compound was obtained as a light brown solid, MS: m/e=322.2(M+H⁺), using chemistry similar to that described in Example 37, step 3from4-methyl-6-(5-trimethylsilanylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one(Example 112, step 2) and 1-fluoro-3-iodobenzene.

Example 114(RS)-5-Methoxy-6,6-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

Step 1: (RS)-3-Benzyloxycarbonylamino-2-methoxy-propionic acid methylester

The title compound was obtained using chemistry similar to thatdescribed in Example 16 starting from(RS)-3-benzyloxycarbonylamino-2-hydroxy-propionic acid methyl ester,which was directly used in the next step without furthercharacterisation.

Step 2: (RS)-5-Methoxy-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a light yellow oil, MS: m/e=160.2(M+H⁺), using procedures similar to those described in Example 95, step2 and Example 72, step 2 from(RS)-3-benzyloxycarbonylamino-2-methoxy-propionic acid methyl ester(Example 114, step 1).

Step 3:(RS)-5-Methoxy-6,6-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a light yellow oil, MS: m/e=337.3(M+H⁺), using chemistry similar to that described in Example 37, step 2from 2-bromo-5-phenylethynyl-pyridine (Example 96, step 1) and(RS)-5-methoxy-6,6-dimethyl-[1,3]oxazinan-2-one (Example 114, step 2).

Example 1154,4-Dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one

Step 1: 2-Methanesulfonyl-5-phenylethynyl-pyrimidine

Bis-(triphenylphosphine)-palladium(II)dichloride (1.48 g, 2.11 mmol,0.05 equiv.) was dissolved in 200 ml THF. (10 g, 42.2 mmol)5-Bromo-2-(methylsulfonyl)pyrimidine and phenylacetylene (9.26 ml, 84.4mmol, 2 equiv.) were added at room temperature. Triethylamine (17.6 ml,127 mmol, 3 equiv.), triphenylphosphine (330 mg, 1.3 mmol, 0.03 equiv.)and copper(I)iodide (80 mg, 420 μmol, 0.01 equiv.) were added and themixture was stirred for 4 hours at 65° C. The reaction mixture wascooled and extracted with saturated NaHCO₃ solution and two times withEtOAc. The organic layers were extracted with water, dried over sodiumsulfate and evaporated to dryness. The crude product was purified byflash chromatography on a silica gel column and eluting with an ethylacetate:heptane gradient 0:100 to 100:0. The desired2-methanesulfonyl-5-phenylethynyl-pyrimidine (6.2 g, 57% yield) wasobtained as a yellow solid, MS: m/e=259.1 (M+H⁺).

Step 2: 4,4-Dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one

(100 mg, 0.39 mmol) 2-Methanesulfonyl-5-phenylethynyl-pyrimidine(Example 115, step 1) was dissolved in 1 ml dioxane.4,4-Dimethylpyrrolidin-2-one (53 mg, 465 μmol, 1.2 equiv.) and cesiumcarbonate (190 mg, 580 μmol, 1.5 equiv.) were added at room temperature.The mixture was stirred for 4 hours at 100° C. The reaction mixture wascooled, evaporated and extracted with saturated NaHCO₃ solution and twotimes with a small volume of dichloromethane. The crude product waspurified by flash chromatography by directly loading the dichloromethanelayers onto a silica gel column and eluting with an ethylacetate:heptane gradient 0:100 to 100:0. The desired4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one (32 mg,28% yield) was obtained as a light yellow solid, MS: m/e=292.1 (M+H⁺).

Example 1165,5-Dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-piperidin-2-one

The title compound was obtained as a brown oil, MS: m/e=306.2 (M+H⁺),using chemistry similar to that described in Example 115, step 2 from2-methanesulfonyl-5-phenylethynyl-pyrimidine (Example 115, step 1) and5,5-dimethylpiperidin-2-one (CAS 4007-79-8).

Example 1172-(5-Phenylethynyl-pyrimidin-2-yl)-2-aza-spiro[4.4]nonan-3-one

The title compound was obtained as a light yellow solid, MS: m/e=318.2(M+H⁺), using chemistry similar to that described in Example 115, step 2from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (Example 115, step 1)and 2-aza-spiro[4.4]nonan-3-one (CAS 75751-72-3).

Example 1181-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

Step 1: 1-(5-Bromo-pyrimidin-2-yl)-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a light yellow solid, MS:m/e=270.1/272.2 (M+H⁺), using chemistry similar to that described inExample 115, step 2 from 5-bromo-2-fluoropyrimidine and4,4-dimethylpyrrolidin-2-one.

Step 2:1-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=310.2(M+H⁺), using chemistry similar to that described in Example 115, step 1from 1-(5-bromo-pyrimidin-2-yl)-4,4-dimethyl-pyrrolidin-2-one (Example118, step 1) and 1-ethynyl-3-fluoro-benzene.

Example 1191-[5-(3-Chloro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

Step 1: 2-Chloro-5-(3-chloro-phenylethynyl)-pyrimidine

The title compound was obtained as a light brown solid, MS: m/e=248/250(M+H⁺), using chemistry similar to that described in Example 115, step 1from 2-chloro-5-iodopyrimidine and 1-chloro-3-ethynyl-benzene.

Step 2:1-[5-(3-Chloro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a light yellow solid, MS:m/e=326.3/328.3 (M+H⁺), using chemistry similar to that described inExample 115, step 2 from 2-chloro-5-(3-chloro-phenylethynyl)-pyrimidine(Example 119, step 1) and 4,4-dimethylpyrrolidin-2-one.

Example 1201-[5-(4-Fluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

Step 1: 2-Bromo-5-trimethylsilanylethynyl-pyrimidine

2-Bromo-5-iodopyrimidine (1.2 g, 4.2 mmol) was dissolved under nitrogenin 25 ml THF. Bis-(triphenylphosphine)-palladium(II)dichloride (300 mg,420 μmol, 0.1 equiv.), ethynyltrimethylsilane (540 mg, 0.77 ml, 5.48mmol, 1.3 equiv.), triethylamine (0.85 g, 1.17 ml, 8.4 mmol, 2 equiv.)and copper(I)iodide (40 mg, 210 μmol, 0.05 equiv.) were added and themixture was stirred for 4 hours at 50° C. The reaction mixture wascooled and evaporated to dryness. The crude product was purified byflash chromatography on silica gel, eluting with an ethylacetate:heptane gradient 0:100 to 40:60. The desired2-bromo-5-trimethylsilanylethynyl-pyrimidine (0.75 g, 70% yield) wasobtained as a yellow solid, MS: m/e=255/257 (M+H⁺).

Step 2:4,4-Dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one

(200 mg, 0.78 mmol) 2-Bromo-5-trimethylsilanylethynyl-pyrimidine(Example 120, step 1) was dissolved in toluene (7 ml) and4,4-dimethylpyrrolidin-2-one (89 mg, 0.78 mmol, 1.0 equiv.), cesiumcarbonate (410 mg, 1.25 mmol, 1.6 equiv.), xantphos (CAS 161265-03-8)(18 mg, 0.03 mmol, 0.04 equiv.) and Pd₂(dba)₃ (14 mg, 0.01 mmol, 0.02equiv.) were added under nitrogen. The mixture was stirred for 2 hoursat 90° C. The crude product was purified by flash chromatography bydirectly loading the toluene mixture onto a silica gel column andeluting with an ethyl acetate:heptane gradient 0:100 to 100:0. Thedesired4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one(164 mg, 73% yield) was obtained as a light red solid, MS: m/e=288.1(M+H⁺).

Step 3:1-[5-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

4,4-Dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one(Example 120, step 2) (30 mg, 0.1 mmol) was dissolved in DMF (1 ml).1-Fluoro-4-iodobenzene (32 mg, 0.14 mmol, 1.4 equiv.), Et₃N (43 μl, 0.31mmol, 3 equiv.), Bis-(triphenylphosphine)-palladium(II)dichloride (4 mg,5.2 μmol, 0.05 equiv.) and copper(I)iodide (0.6 mg, 3.1 μmol, 0.03equiv.) were added under nitrogen and the mixture was heated to 70° C.TBAF 1M in THF (115 μl, 0.115 mmol, 1.1 equiv.) was added dropwise in 20minutes at 70° C. The reaction mixture was stirred for 30 minutes at 70°C. and evaporated with isolute to dryness. The crude product waspurified by flash chromatography with a 20 g silica gel column andeluting with heptane:ethyl acetate 100:0->0:100. The desired1-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one(24 mg, 73% yield) was obtained as a white solid, MS: m/e=310.1 (M+H⁺).

Example 1211-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a white solid, MS: m/e=328.2 (M+H⁺),using chemistry similar to that described in Example 120, step 3 from4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one(Example 120, step 2) and 1,4-difluoro-2-iodobenzene.

Example 1223,4,4-Trimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-imidazolidin-2-one

Step 1: 1-(5-Iodo-pyrimidin-2-yl)-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=319(M+H⁺), using chemistry similar to that described in Example 115, step 2from 2-chloro-5-iodopyrimidine and 4,4-dimethyl-imidazolidin-2-one (CAS24572-33-6).

Step 2: 1-(5-Iodo-pyrimidin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one

(55 mg, 173 μmol)1-(5-Iodo-pyrimidin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example 122,step 1) was dissolved in DMF (1 ml) and cooled to 0-5° C. NaH (55%) (9mg, 225 μmol, 1.3 equiv.) was added and the mixture was stirred for 30min at 0-5° C. Iodomethane (13 μl, 200 μmol, 1.2 equiv.) was added andthe mixture was stirred for 30 min without cooling bath. The reactionmixture was treated with sat. NaHCO₃ solution and extracted twice with asmall volume of CH₂Cl₂. The organic layers were loaded directly tosilica gel column and the crude material was purified by flashchromatography on silica gel (20 gr, ethyl acetate/heptane gradient,0:100 to 100:0). The desired1-(5-iodo-pyrimidin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (31 mg, 54%yield) was obtained as a white solid, MS: m/e=333.1 (M+H⁺).

Step 3:3,4,4-Trimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-imidazolidin-2-one

The title compound was obtained as a yellow oil, MS: m/e=307.4 (M+H⁺),using chemistry similar to that described in Example 115, step 1 from1-(5-iodo-pyrimidin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example122, step 2) and phenylacetylene.

Example 1231-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=325.2(M+H⁺), using chemistry similar to that described in Example 115, step 1from 1-(5-iodo-pyrimidin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one(Example 122, step 2) and 1-ethynyl-3-fluoro-benzene.

Example 1241-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

Step 1:4,4-Dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=289.0(M+H⁺), using chemistry similar to that described in Example 120, step 2from 2-bromo-5-trimethylsilanylethynyl-pyrimidine (Example 120, step 1)and 4,4-dimethyl-imidazolidin-2-one (CAS 24572-33-6).

Step 2:1-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=329.2(M+H⁺), using chemistry similar to that described in Example 120, step 3from4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-imidazolidin-2-one(Example 124, step 1) and 1,4-difluoro-2-iodobenzene.

Step 3:1-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=343.1 (M+H⁺),using chemistry similar to that described in Example 122, step 2 from1-[5-(2,5-difluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-imidazolidin-2-one(Example 124, step 2) and iodomethane.

Example 1251-[5-(4-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=325.2(M+H⁺), using chemistry similar to that described in Example 115, step 1from 1-(5-iodo-pyrimidin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one(Example 122, step 2) and 1-ethynyl-4-fluoro-benzene.

Example 1261-[5-(3,4-Difluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=343.1(M+H⁺), using chemistry similar to that described in Example 115, step 1from 1-(5-iodo-pyrimidin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one(Example 122, step 2) and 4-ethynyl-1,2-difluoro-benzene.

Example 127(RS)-3-Methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one

Step 1:(RS)-4-Iodo-N-(5-iodo-pyrimidin-2-yl)-2-methoxy-3,3-dimethyl-butyramide

The title compound was obtained as an orange solid, MS: m/e=476.0(M+H⁺), using chemistry similar to that described in patent WO9637466,page 17, step 2 starting from(RS)-3-methoxy-4,4-dimethyl-dihydro-furan-2-one (CAS 100101-82-4)instead of 3-t-butylcarbamoyloxy-tetrahydrofuran-2-one and by using2-amino-5-iodopyrimidine instead of 2-amino-4-trifluoromethylpyridine.

Step 2:(RS)-1-(5-Iodo-pyrimidin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=348.0(M+H⁺), using chemistry similar to that described in patent WO9637466,page 17, step 3 from(RS)-4-iodo-N-(5-iodo-pyrimidin-2-yl)-2-methoxy-3,3-dimethyl-butyramide(Example 127, step 1).

Step 3:(RS)-3-Methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=322.2(M+H⁺), using chemistry similar to that described in Example 115, step 1from(RS)-1-(5-iodo-pyrimidin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one(Example 127, step 2) and phenylacetylene.

Example 128 (5R or5S)-5-Methoxymethyl-3-(5-phenylethynyl-pyrimidin-2-yl)-oxazolidin-2-one

The title compound, a light yellow solid, MS: m/e=322.3 (M+H⁺), wasprepared by separation of(RS)-3-methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one(Example 127) using a chiral column (chiralpak AD withheptane:isopropanol 90:10 as solvent).

Example 129 (5S or5R)-5-Methoxymethyl-3-(5-phenylethynyl-pyrimidin-2-yl)-oxazolidin-2-one

The title compound, a light yellow solid, MS: m/e=322.3 (M+H⁺), wasprepared by separation of(RS)-3-methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one(Example 127) using a chiral column (chiralpak AD withheptane:isopropanol 90:10 as solvent).

Example 130(RS)-1-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=340.2 (M+H⁺),using chemistry similar to that described in Example 115, step 1 from(RS)-1-(5-iodo-pyrimidin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one(Example 127, step 2) and 1-ethynyl-3-fluoro-benzene.

Example 131 (R orS)-1-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound, a white solid, MS: m/e=340.3 (M+H⁺), was prepared byseparation of(RS)-1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one(Example 130) using a chiral column (chiralpak AD withheptane:isopropanol 90:10 as solvent).

Example 132 (S orR)-1-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound, a white solid, MS: m/e=340.3 (M+H⁺), was prepared byseparation of(RS)-1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one(Example 130) using a chiral column (chiralpak AD withheptane:isopropanol 90:10 as solvent).

Example 133 (R orS)-1-[5-(2,3-Difluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

Step 1:(RS)-3-Methoxy-4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=318.1(M+H⁺), using chemistry similar to that described in Example 115, step 1from(RS)-1-(5-iodo-pyrimidin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one(Example 127, step 2) and ethynyl-trimethyl-silane.

Step 2:(RS)-1-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=358.1 (M+H⁺),using chemistry similar to that described in Example 120, step 3 from(RS)-3-methoxy-4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one(Example 133, step 1) and 1,4-difluoro-2-iodo-benzene.

Step 3: (R orS)-1-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound, a white solid, MS: m/e=358.1 (M+H⁺), was prepared byseparation of(RS)-1-[5-(2,5-difluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one(Example 133, step 2) using a chiral column (Reprosil Chiral NR withheptane:EtOH 70:30 as solvent).

Example 1344,4-Dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-piperidin-2-one

Step 1:4,4-Dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-piperidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=302.2(M+H⁺), using chemistry similar to that described in Example 115, step 1from 2 from 2-bromo-5-trimethylsilanylethynyl-pyrimidine (Example 120,step 1) and 4,4-dimethyl-piperidin-2-one (CAS 55047-81-9).

Step 2: 4,4-Dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-piperidin-2-one

The title compound was obtained as a white solid, MS: m/e=306.3 (M+H⁺),using chemistry similar to that described in Example 120, step 3 from4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-piperidin-2-one(Example 134, step 1) and iodobenzene.

Example 1351-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-piperidin-2-one

The title compound was obtained as a white solid, MS: m/e=324.2 (M+H⁺),using chemistry similar to that described in Example 120, step 3 from4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-piperidin-2-one(Example 134, step 1) and 1-fluoro-3-iodobenzene.

Example 1361-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-piperidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=342.3(M+H⁺), using chemistry similar to that described in Example 120, step 3from4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-piperidin-2-one(Example 134, step 1) and 2,5-difluoro-3-iodobenzene.

Example 1373,4,4-Trimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

Step 1: 4,4-Dimethyl-tetrahydro-pyrimidin-2-one

(3.4 g, 14.3 mmol) (3-Amino-3-methyl-butyl)-carbamic acid tert-butylester hydrochloride was dissolved in THF (60 ml) and KOtBu (6.4 g, 57.1mmol, 4 equiv.) was added. The mixture was stirred for 16 hours at 60°C. and evaporated then with isolute to dryness. The crude product waspurified by flash chromatography by directly loading the residue onto asilica gel column and eluting with an ethyl acetate:methanol gradient100:0 to 70:30. The desired 4,4-dimethyl-tetrahydro-pyrimidin-2-one(1.65 g, 90% yield) was obtained as a light yellow solid, MS: m/e=129.1(M+H⁺).

Step 2:4,4-Dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

The title compound was obtained as a brown solid, MS: m/e=303.2 (M+H⁺),using chemistry similar to that described in Example 120, step 2 from 2from 2-bromo-5-trimethylsilanylethynyl-pyrimidine (Example 120, step 1)and 4,4-dimethyl-tetrahydro-pyrimidin-2-one (Example 137, step 1).

Step 3:4,4-Dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

The title compound was obtained as a yellow solid, MS: m/e=329.2 (M+H⁺),using chemistry similar to that described in Example 120, step 3 from4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one(Example 137, step 2) and iodobenzene.

Step 4:3,4,4-Trimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

The title compound was obtained as a light yellow solid, MS: m/e=321.1(M+H⁺), using chemistry similar to that described in Example 122, step 2from4,4-dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one(Example 137, step 3) and iodomethane.

Example 1385′-(3-Fluoro-phenylethynyl)-3,4,4-trimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

Step 1:5′-(3-Fluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

The title compound was obtained as a light brown solid, MS: m/e=325.2(M+H⁺), using chemistry similar to that described in Example 120, step 3from4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one(Example 137, step 2) and 1-fluoro-3-iodobenzene.

Step 2:5′-(3-Fluoro-phenylethynyl)-3,4,4-trimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

The title compound was obtained as a yellow oil, MS: m/e=339.2 (M+H⁺),using chemistry similar to that described in Example 122, step 2 from5′-(3-fluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one(Example 138, step 1) and iodomethane.

Example 1395′-(2,5-Difluoro-phenylethynyl)-3,4,4-trimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

Step 1:5′-(2,5-Difluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

The title compound was obtained as a light brown solid, MS: m/e=343.1(M+H⁺), using chemistry similar to that described in Example 120, step 3from4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one(Example 137, step 2) and 1,4-difluoro-2-iodobenzene.

Step 2:5′-(2,5-Difluoro-phenylethynyl)-3,4,4-trimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

The title compound was obtained as a light yellow solid, MS: m/e=357.2(M+H⁺), using chemistry similar to that described in Example 122, step 2from5′-(2,5-difluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one(Example 139, step 1) and iodomethane.

Example 1403-Isopropyl-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-imidazolidin-2-one

Step 1:1-(5-Iodo-pyrimidin-2-yl)-3-isopropyl-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow oil, MS: m/e=361.0(M+H⁺), using chemistry similar to that described in Example 122, step 2from 1-(5-iodo-pyrimidin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example122, step 1) and 2-iodopropane.

Step 2:3-Isopropyl-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=335.2(M+H⁺), using chemistry similar to that described in Example 115, step 1from1-(5-iodo-pyrimidin-2-yl)-3-isopropyl-4,4-dimethyl-imidazolidin-2-one(Example 140, step 1) and phenylacetylene.

Example 1411-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3-isopropyl-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=353.3(M+H⁺), using chemistry similar to that described in Example 115, step 1from1-(5-iodo-pyrimidin-2-yl)-3-isopropyl-4,4-dimethyl-imidazolidin-2-one(Example 140, step 1) and 1-ethynyl-3-fluorobenzene.

Example 1421-[5-(4-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3-isopropyl-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=353.3(M+H⁺), using chemistry similar to that described in Example 115, step 1from1-(5-iodo-pyrimidin-2-yl)-3-isopropyl-4,4-dimethyl-imidazolidin-2-one(Example 140, step 1) and 1-ethynyl-4-fluorobenzene.

Example 1431-[5-(4-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3-ethyl-4,4-dimethyl-imidazolidin-2-one

Step 1: 1-(5-Bromo-pyrimidin-2-yl)-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS:m/e=271.1/273.1 (M+H⁺), using chemistry similar to that described inExample 120, step 2 from 5-bromo-2-iodopyrimidine and4,4-dimethyl-imidazolidin-2-one (CAS 24572-33-6).

Step 2:1-(5-Bromo-pyrimidin-2-yl)-3-ethyl-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a brown solid, MS: m/e=299.2/301.2(M+H⁺), using chemistry similar to that described in Example 122, step 2from 1-(5-bromo-pyrimidin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example143, step 1) and ethyl iodide.

Step 3:1-(5-Iodo-pyrimidin-2-yl)-3-ethyl-4,4-dimethyl-imidazolidin-2-one

(350 mg, 1.17 mmol)1-(5-Bromo-pyrimidin-2-yl)-3-ethyl-4,4-dimethyl-imidazolidin-2-one(Example 143, step 2) was dissolved in dioxane (20 ml) and sodium iodide(700 mg, 4.68 mmol, 4 equiv.), copper(I)iodide (21 mg, 0.234 mmol, 0.2equiv.) and trans-N,N′-dimethylcyclohexane-1,2-diamine (33 mg, 37 μl,0.234 mmol, 0.2 equiv.) were added. The mixture was stirred for 16 hoursat 100° C. The reaction mixture was cooled and extracted with saturatedNaHCO₃ solution and two times ethyl acetate. The organic layers wereextracted with brine, dried over sodium sulfate and evaporated todryness. The desired1-(5-iodo-pyrimidin-2-yl)-3-ethyl-4,4-dimethyl-imidazolidin-2-one (350mg, 86% yield) was obtained as a brown solid, MS: m/e=347.0 (M+H⁺) andwas used without further purification in the next step.

Step 4:1-[5-(4-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3-ethyl-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a brown solid, MS: m/e=339.3 (M+H⁺),using chemistry similar to that described in Example 115, step 1 from1-(5-iodo-pyrimidin-2-yl)-3-ethyl-4,4-dimethyl-imidazolidin-2-one(Example 143, step 3) and 1-ethynyl-4-fluorobenzene.

Example 1441-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3-ethyl-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=339.3(M+H⁺), using chemistry similar to that described in Example 115, step 1from 1-(5-iodo-pyrimidin-2-yl)-3-ethyl-4,4-dimethyl-imidazolidin-2-one(Example 143, step 3) and 1-ethynyl-3-fluorobenzene.

Example 145(RS)-5,6,6-Trimethyl-3-(5-phenylethynyl-pyrimidin-2-yl)-[1,3]oxazinan-2-one

Step 1: (RS)-(3-Hydroxy-2,3-dimethyl-butyl)-carbamic acid tert-butylester

The title compound was obtained as a colorless oil, MS: m/e=218.3(M+H⁺), using chemistry similar to that described in Example 95, step 2from methyl 3-(tert-butoxycarbonylamino)-2-methylpropanoate (CAS182486-16-4).

Step 2: (RS)-5,6,6-Trimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a yellow solid, MS: m/e=144.0 (M+H⁺),using chemistry similar to that described in Example 72, step 2 from(RS)-(3-hydroxy-2,3-dimethyl-butyl)-carbamic acid tert-butyl ester(Example 145, step 1).

Step 3: 2-Bromo-5-phenylethynyl-pyrimidine

The title compound was obtained as a white solid using chemistry similarto that described in Example 120, step 1 from 2-bromo-5-iodopyrimidineand phenylacetylene.

Step 4:(RS)-5,6,6-Trimethyl-3-(5-phenylethynyl-pyrimidin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a yellow solid, MS: m/e=322.2 (M+H⁺),using chemistry similar to that described in Example 120, step 2 from2-bromo-5-phenylethynyl-pyrimidine (Example 145, step 3) and(RS)-5,6,6-trimethyl-[1,3]oxazinan-2-one (Example 145, step 2).

Example 146(RS)-3-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-5,6,6-trimethyl-[1,3]oxazinan-2-one

Step 1:(RS)-5,6,6-Trimethyl-3-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a brown solid, MS: m/e=318.1 (M+H⁺),using chemistry similar to that described in Example 120, step 2 from2-bromo-5-trimethylsilanylethynyl-pyrimidine (Example 120, step 1) and(RS)-5,6,6-trimethyl-[1,3]oxazinan-2-one (Example 145, step 2).

Step 2:(RS)-3-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-5,6,6-trimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a white solid, MS: m/e=358.4 (M+H⁺),using chemistry similar to that described in Example 120, step 3 from(RS)-5,6,6-trimethyl-3-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-[1,3]oxazinan-2-one(Example 146, step 1) and 1,4-difluoro-2-iodobenzene.

Example 1474-Methyl-6-(5-phenylethynyl-pyrimidin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one

Step 1: 4-Methyl-4,6-diaza-spiro[2.4]heptan-5-one

The title compound was obtained as a white solid using proceduressimilar to those described in Example 106, step 1 to 3 from startingfrom 1-((tert-butoxycarbonylamino)methyl)cyclopropanecarboxylic acidinstead of (rac)-cis-2-(tert-butoxycarbonylamino)cyclopentanecarboxylicacid.

Step 2:4-Methyl-6-(5-phenylethynyl-pyrimidin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one

The title compound was obtained as a white solid, MS: m/e=305.3 (M+H⁺),using chemistry similar to that described in Example 120, step 2 from2-bromo-5-phenylethynyl-pyrimidine (Example 145, step 3) and4-methyl-4,6-diaza-spiro[2.4]heptan-5-one (Example 147, step 1).

Example 148(RS)-3-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-5,6,6-trimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a yellow solid, MS: m/e=340.1 (M+H⁺),using chemistry similar to that described in Example 120, step 3 from(RS)-5,6,6-trimethyl-3-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-[1,3]oxazinan-2-one(Example 146, step 1) and 1-fluoro-3-iodobenzene.

Example 149(RS)-3-[5-(4-Fluoro-phenylethynyl)-pyrimidin-2-yl]-5,6,6-trimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a yellow solid, MS: m/e=340.1 (M+H⁺),using chemistry similar to that described in Example 120, step 3 from(RS)-5,6,6-trimethyl-3-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-[1,3]oxazinan-2-one(Example 146, step 1) and 1-fluoro-4-iodobenzene.

Example 1504,4-Dimethyl-1-(6-(phenylethynyl)pyridazin-3-yl)pyrrolidin-2-one

To a solution of 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5)(180 mg, 839 μmol) and 4,4-dimethylpyrrolidin-2-one (CAS 66899-02-3)(142 mg, 1.26 mmol, 1.5 equiv.) in 2 ml of DMF were added cesiumcarbonate (546 mg, 1.68 mmol, 2 equiv.). The suspension was heated 16hours at 120° C. and then allowed to cool to room temperature. Ethylacetate (10 ml) were added and the unsoluble salts were filtered off.After concentration in vaccuo, the residue was dissolved in 10 ml ofethyl acetate. Silicagel (4 g) were added and the suspension wasevaporated to dryness. The silicagel with the adsorbed crude mixture wasloaded onto a 20 g silicagel flash chromatography column and elutedthree min. with heptane followed by a heptane to 45% ethylacetate/heptane gradient over 25 min to yield 36 mg (15% yield) of thetitle compound as a crystalline yellow solid, MS: m/e=292.3 (M+H⁺).

Example 1514,4-Dimethyl-1-(6-(phenylethynyl)pyridazin-3-yl)piperidin-2-one

Step 1: 3-Iodo-6-(phenylethynyl)pyridazine

To a solution of 100 mg (0.466 mmol) of3-chloro-6-(phenylethynyl)pyridazine in 5 ml of acetonitrile were addedsodium iodide (209 mg, 1.4 mmol, 3 equiv.), acetic acid (56 mg, 53.3 ml,0.93 mmol, 2 equiv.), and 95% sulfuric acid (4.6 mg, 2.5 ml, 0.47 mmol,1 equiv.). The orange solution was stirred for 8 hours at 70° C. andthen left to cool overnight. After standard workup with ethylacetate/water, the residue was adsorbed onto 4 g of silicagel andpurified by flash chromatography over a 20 g silicagel column over aheptane to 50% ethyl acetate in heptane gradient to yield 82 mg (58%yield) of the title compound as a crystalline light yellow solid, MS:m/e=307.1 (M+H⁺).

Step 2: 4,4-Dimethyl-1-(6-(phenylethynyl)pyridazin-3-yl)piperidin-2-one

To a well stirred suspension of 3-iodo-6-(phenylethynyl)pyridazine(Example 151, step 1) (80 mg, 261 μmol), 4,4-dimethylpiperidin-2-one(66.5 mg, 314 μmol, 1.2 equiv.) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (6.05 mg,10.5 μmol, 0.04 equiv.) in 2 ml of toluene were added under argonatmosphere tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃), (4.79mg, 5.23 μmol, 0.02 equiv.) and the mixture was stirred for 4 hours at100° C. The crude mixture was directly purified by flash chromatographyover a 20 g silicagel column using a heptane to 50% ethyl acetate inheptane gradient, and yielded 18 mg (23% yield) of the title compound asa white solid, MS: m/e=306.2 (M+H⁺).

Example 1525,5-Dimethyl-3-(6-(phenylethynyl)pyridazin-3-yl)oxazolidin-2-one

Step 1: 2-Methyl-1-(6-phenylethynyl-pyridazin-3-ylamino)-propan-2-ol

A solution of 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5) (300mg, 1.4 mmol) and 1-amino-2-methylpropan-2-ol (137 mg, 147 μl, 1.54mmol, 1.1 equiv.) in 3 ml of pyridine was heated 20 hours at 120° C. ina sealed tube. The solvent was removed in vaccuo. The residue was takenup in ethyl acetate/methanol, adsorbed onto 4 g of silica and purifiedon a 20 g flash chromatography column using a heptane to ethyl acetategradient to yield 90 mg (24% yield) of the title compound as acrystalline light yellow solid, MS: m/e=268.2 (M+H⁺).

Step 2: 5,5-Dimethyl-3-(6-(phenylethynyl)pyridazin-3-yl)oxazolidin-2-one

A solution of2-methyl-1-(6-(phenylethynyl)pyridazin-3-ylamino)propan-2-ol (Example152, step 1) (90 mg, 337 μmol) and triethylamine (102 mg, 141 μl, 1.01mmol, 3 equiv.) in 4 ml of THF was cooled to 0-5° C. and thentriphosgene (99.9 mg, 337 μmol, 1 equiv.) was added and the reaction wasstirred for 1 hour at 0-5° C. The mixture was quenched with 5 ml of 5%sodium bicarbonate solution and worked up with ethyl acetate/water. Thecrude material was adsorbed onto silicagel and purified by flashchromatography over a heptane to 50% ethyl acetate in heptane gradientto yield the title compound (51 mg, 52% yield) as a crystalline lightyellow solid, MS: m/e=294.2 (M+H⁺).

Example 1536,6-Dimethyl-3-(6-(phenylethynyl)pyridazin-3-yl)-1,3-oxazinan-2-one

Step 1: 2-Methyl-4-(6-phenylethynyl-pyridazin-3-ylamino)-butan-2-ol

A solution of 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5) (125mg, 0.582 mmol) and 4-amino-2-methylbutan-2-ol hydrochloride (244 mg,1.75 mmol, 3 equiv.) and triethylamine (206 mg, 284 ml, 2.04 mmol, 2equiv.) in 1.25 ml of pyridine was heated 20 hours at 85° C. The solventwas removed in vaccuo. The residue was taken up in ethylacetate/methanol, adsorbed onto 4 g of silica and purified on a 20 gflash chromatography column using a heptane/ethyl acetate 85:15 to 15:85gradient to yield 44 mg (27% yield) of the title compound as acrystalline white solid, MS: m/e=282.2 (M+H⁺).

Step 2:6,6-Dimethyl-3-(6-(phenylethynyl)pyridazin-3-yl)-1,3-oxazinan-2-one

The title compound, a crystalline light yellow solid, MS: m/e=308.3(M+H⁺), was prepared in accordance with the general method of Example152, step 2 starting from2-methyl-4-(6-phenylethynyl-pyridazin-3-ylamino)-butan-2-ol (Example153, step 1) and triphosgene.

Example 1543,4,4-Trimethyl-1-(6-(m-tolylethynyl)pyridazin-3-yl)imidazolidin-2-one

Step 1: N-1-(6-Iodo-pyridazin-3-yl)-2-methyl-propane-1,2-diamine

A suspension of 3-chloro-6-iodo-pyridazine (CAS 135034-10-5) (500 mg,2.08 mmol) and 2-methylpropane-1,2-diamine (220 mg, 262 μl, 2.5 mmol,1.2 equiv.) in 4 ml of pyridine was heated 16 hours at 100° C. Thesolvent was removed in vaccuo. The crude material (508 mg) was directlyused in the next step.

Step 2: 1-(6-Chloro-pyridazin-3-yl)-4,4-dimethyl-imidazolidin-2-one

To a solution of crudeN-1-(6-iodopyridazin-3-yl)-2-methylpropane-1,2-diamine (Example 154,step 1) (580 mg, 1.99 mmol) and pyridine (346 mg, 353 μl, 4.37 mmol, 2.2equiv.) in 5 ml of dichloromethane were added (1.96 g, 2.1 ml, 3.97mmol, 2 equiv.) of a 20% solution of phosgene in toluene dropwise at0-2° C. over a period of 10 min. After stirring for 2 hours at 0-4° C.,the reaction was allowed to warm up to room temperature overnight. Themixture was quenched with 5 ml of 5% sodium bicarbonate solution andworked up with dichloromethane/water. The crude material was adsorbedonto silicagel and purified by flash chromatography using a heptane to80% ethyl acetate in heptane gradient to yield the title compound (wherethe iodine was completely exchanged for chlorine) (140 mg, 31% yield) asa crystalline white solid, MS: m/e=227.2, 229.4 (M+H⁺).

Step 3: 1-(6-Chloro-pyridazin-3-yl)-3,4,4-trimethyl-imidazolidin-2-one

To a solution of1-(6-chloropyridazin-3-yl)-4,4-dimethylimidazolidin-2-one (Example 154,step 2) (140 mg, 618 μmol) in DMF (3 ml) was added 60% sodium hydridesuspension (37.1 mg, 926 μmol, 1.5 equiv.). After stirring at roomtemperature for 10 min, iodomethane (132 mg, 57.9 μl, 926 μmol, 1.5equiv.) was added and the suspension was stirred for 1 hour at roomtemperature. The solvent was removed in vaccuo and the residue wasworked up with ethyl acetate/water. The title compound was obtained as acrystalline light brown solid (129 mg, 87% yield), MS: m/e=241.2, 243.4(M+H⁺).

Step 4: 1-(6-Iodo-pyridazin-3-yl)-3,4,4-trimethyl-imidazolidin-2-one

The title compound, crystalline light yellow solid (149 mg, 86%), MS:m/e=333.0 (M+H⁺), was prepared from1-(6-chloro-pyridazin-3-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example154, step 3) in accordance with the general method of Example 151, step1 by acid catalyzed chlorine-iodine exchange.

Step 5:3,4,4-Trimethyl-1-(6-(m-tolylethynyl)pyridazin-3-yl)imidazolidin-2-one

To a solution of1-(6-iodopyridazin-3-yl)-3,4,4-trimethylimidazolidin-2-one (Example 154,step 4) (75 mg, 226 μmol), 1-ethynyl-3-methylbenzene (44.6 mg, 49.5 μl,384 μmol, 1.7 equiv.), triethylamine (68.5 mg, 94.4 μl, 677 μmol, 3equiv.), bis(triphenylphosphine)palladium (II) chloride (9.51 mg, 13.5μmol, 0.06 equiv.) and triphenylphosphine (1.78 mg, 6.77 μmol, 0.03equiv.) in 2 ml of THF was added under an Argon atmosphere copper (I)iodide (1.29 mg, 6.77 μmol, 0.03 equiv.). The suspension was warmed to60° C. for 2 hours, taken up in 5 ml of ethyl acetate and adsorbed on 4g of silica. Purification by flash chromatography on silicagel using aheptane to 50% ethyl acetate/heptane gradient yielded the title compoundas a crystalline light yellow solid (18 mg, 25% yield), MS: m/e=321.2(M+H⁺).

Example 1551-(6-((3-Chlorophenyl)ethynyl)pyridazin-3-yl)-3,4,4-trimethylimidazolidin-2-one

The title compound, a crystalline light yellow solid (36 mg, 47% yield),MS: m/e=341.2, 343.3 (M+H⁺), was prepared in accordance with the generalmethod of Example 154, step 5; starting from1-(6-iodo-pyridazin-3-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example154, step 4) and 3-chlorophenyl-acetylene.

Example 1563,4,4-Trimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)imidazolidin-2-one

Step 1: N-1-(5-Iodo-pyrazin-2-yl)-2-methyl-propane-1,2-diamine

To a solution of 2-bromo-5-iodopyrazine (CAS 622392-04-5) (250 mg, 878μmol) in 0.7 ml of pyridine, was added 2-methylpropane-1,2-diamine (116mg, 138 μl, 1.32 mmol, 1.5 equiv.) at room temperature. The colorlesssolution was stirred for 16 hours at 100° C. The reaction mixture wascooled and concentrated in vacuo. The crude material was used directlyin the next step.

Step 2: 1-(5-Iodo-pyrazin-2-yl)-4,4-dimethyl-imidazolidin-2-one

The title compound, an off-white solid (72 mg, 26% yield), was preparedin accordance with the general method of Example 154, step 2; startingfrom N-1-(5-iodo-pyrazin-2-yl)-2-methyl-propane-1,2-diamine (Example156, step 1) and cyclisation with phosgene. The crude material wasdirectly used in the next step without further characterization.

Step 3: 1-(5-Iodo-pyrazin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one

The title compound, an off-white solid (77 mg, 99% yield), was preparedin accordance with the general method of Example 154, step 3; byalkylation of 1-(5-iodo-pyrazin-2-yl)-4,4-dimethyl-imidazolidin-2-one(Example 156, step 2) with methyl iodide. The crude material wasdirectly used in the next step without further characterization.

Step 4:′3,4,4-Trimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)imidazolidin-2-one

The title compound, a crystalline light yellow solid (69 mg, 75% yield),MS: m/e=307.3 (M+H⁺), was prepared in accordance with the general methodof Example 154, step 5; starting from1-(5-iodo-pyrazin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 156,step 3) and phenylacetylene.

Example 1573,4,4-Trimethyl-1-(5-(pyridin-3-ylethynyl)pyrazin-2-yl)imidazolidin-2-one

The title compound, a crystalline yellow solid, MS: m/e=308.3 (M+H⁺),was prepared in accordance with the general method of Example 154, step5; starting from1-(5-iodo-pyrazin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 156,step 3) and 3-pyridylacetylene.

Example 1581-(5-((3-Fluorophenyl)ethynyl)pyrazin-2-yl)-3,4,4-trimethylimidazolidin-2-one

The title compound, a crystalline light yellow solid, MS: m/e=325.2(M+H⁺), was prepared in accordance with the general method of Example154, step 5; starting from1-(5-iodo-pyrazin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 156,step 3) and 3-fluorophenylacetylene.

Example 1591-(5-((4-Fluorophenyl)ethynyl)pyrazin-2-yl)-3,4,4-trimethylimidazolidin-2-one

The title compound, a light yellow solid, MS: m/e=325.2 (M+H⁺), wasprepared in accordance with the general method of example 154, step 5;starting from 1-(5-iodo-pyrazin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one(Example 156, step 3) and 4-fluorophenylacetylene.

Example 1604,4-Dimethyl-1-(5-(pyridin-3-ylethynyl)pyrazin-2-yl)pyrrolidin-2-one

Step 1: 1-(5-Bromo-pyrazin-2-yl)-4,4-dimethyl-pyrrolidin-2-one

To a well stirred suspension of 2-bromo-5-iodopyrazine (300 mg, 1.05mmol), 4,4-dimethylpiperidin-2-one (155 mg, 1.37 mmol, 1.3 equiv.) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (24.4 mg,0.042 mmol, 0.04 equiv.) in 4 ml of toluene were added under argonatmosphere tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃), (19.3mg, 0.021 mmol, 0.02 equiv.) and the mixture was stirred for 5 hours at100° C. The crude mixture was adsorbed on silicagel and purified byflash chromatography over a 20 g silicagel column using a 2:1heptane/ethyl acetate mixture as eluant. The title compound (151 mg, 53%yield) was obtained as a white solid, MS: m/e=270.1, 272.1 (M+H⁺).

Step 2:4,4-Dimethyl-1-(5-(pyridin-3-ylethynyl)pyrazin-2-yl)pyrrolidin-2-one

The title compound, a light yellow solid, MS: m/e=310.4 (M+H⁺), wasprepared in accordance with the general method of Example 154, step 5;starting from 1-(5-bromo-pyrazin-2-yl)-4,4-dimethyl-pyrrolidin-2-one(Example 160, step 1) and 3-fluorophenylacetylene.

Example 1611-(5-((3-Fluorophenyl)ethynyl)pyrazin-2-yl)-4,4-dimethylpiperidin-2-one

Step 1: 1-(5-Bromo-pyrazin-2-yl)-4,4-dimethyl-piperidin-2-one

The title compound, an off-white solid, MS: m/e=284.2, 286.0 (M+H⁺), wasprepared in accordance with the general method of Example 160, step 1;starting from 2-bromo-5-iodopyrazine and 4,4-dimethyl-piperidin-2-one.

Step 2:1-(5-((3-Fluorophenyl)ethynyl)pyrazin-2-yl)-4,4-dimethylpiperidin-2-one

The title compound, an off-white solid, MS: m/e=324.3 (M+H⁺), wasprepared in accordance with the general method of Example 154, step 5;starting from 1-(5-bromo-pyrazin-2-yl)-4,4-dimethyl-piperidin-2-one(Example 161, step 1) and 3-fluorophenylacetylene.

Example 1624,4-Dimethyl-1-(5-(pyridin-3-ylethynyl)pyrazin-2-yl)piperidin-2-one

The title compound, an off-white solid, MS: m/e=307.2 (M+H⁺), wasprepared in accordance with the general method of Example 154, step 5;starting from 1-(5-bromo-pyrazin-2-yl)-4,4-dimethyl-piperidin-2-one(Example 161, step 1) and 3-pyridylacetylene.

Example 1634,4-Dimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)piperidin-2-one

The title compound, a yellow solid, MS: m/e=306.2 (M+H⁺), was preparedin accordance with the general method of Example 154, step 5; startingfrom 1-(5-bromo-pyrazin-2-yl)-4,4-dimethyl-piperidin-2-one (Example 161,step 1) and phenylacetylene.

Example 1644,4-Dimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)tetrahydropyrimidin-2(1H)-one

Step 1: 1-(5-Bromo-pyrazin-2-yl)-4,4-dimethyl-tetrahydro-pyrimidin-2-one

The title compound, a light brown solid, MS: m/e=285.0, 287.0 (M+H⁺),was prepared in accordance with the general method of Example 160, step1; starting from 2-bromo-5-iodopyrazine and4,4-dimethyl-tetrahydro-pyrimidin-2-one (Example 137, step 1).

Step 2:4,4-Dimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)tetrahydropyrimidin-2(1H)-one

The title compound, a light yellow solid, MS: m/e=307.3 (M+H⁺), wasprepared in accordance with the general method of example 45, step 5;starting from1-(5-bromo-pyrazin-2-yl)-4,4-dimethyl-tetrahydro-pyrimidin-2-one(Example 164, step 1) and phenylacetylene.

Example 1653,4,4-Trimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)tetrahydropyrimidin-2(1H)-one

To a solution of4,4-dimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)tetrahydropyrimidin-2(1H)-one(Example 164, step 2) (30 mg, 0.098 mmol) in 2 ml of DMF was added 60%sodium hydride suspension (4.7 mg, 0.118 mmol, 1.2 equiv.). Afterstirring at room temperature for 15 min, iodomethane (7.4 ml, 16.7 mg,0.118 mmol, 1.2 equiv.) was added and the reaction was stirred at roomtemperature overnight. The reaction mixture was concentrated in vacuoand was worked up with ethyl acetate/water. Flash chromatography over aprepacked 20 g silica column eluting with a heptane to 50% ethyl acetatein heptane gradient yielded the title compound (25.4 mg, 81% yield) asan off-white solid, MS: m/e=321.3 (M+H⁺).

Example 1661-(5-((3-Fluorophenyl)ethynyl)pyrazin-2-yl)-4,4-dimethyltetrahydropyrimidin-2(1H)-one

The title compound, an off-white solid, MS: m/e=325.3 (M+H⁺), wasprepared in accordance with the general method of Example 154, step 5;starting from1-(5-bromo-pyrazin-2-yl)-4,4-dimethyl-tetrahydro-pyrimidin-2-one(Example 164, step 1) and 3-fluorophenylacetylene.

Example 1671-(5-((3-Fluorophenyl)ethynyl)pyrazin-2-yl)-3,4,4-trimethyltetrahydropyrimidin-2(1H)-one

The title compound, a light yellow solid, MS: m/e=339.1 (M+H⁺), wasprepared in accordance with the general method of Example 165, byalkylation of1-(5-((3-fluorophenyl)ethynyl)pyrazin-2-yl)-4,4-dimethyltetrahydropyrimidin-2(1H)-one(Example 166) with methyl iodide.

Example 1686,6-Dimethyl-3-(5-(phenylethynyl)pyrazin-2-yl)-1,3-oxazinan-2-one

Step 1: 2-Bromo-5-phenylethynyl-pyrazine

To a solution of 2-bromo-5-iodopyrazine (500 mg, 1.76 mmol),phenylacetylene (224 mg, 241 μl, 2.19 mmol, 1.25 equiv.), triethylamine(533 mg, 734 μl, 5.27 mmol, 3 equiv.), bis(triphenylphosphine)palladium(II) chloride (73.9 mg, 0.105 mmol, 0.06 equiv.) and triphenyl-phosphine(13.8 mg, 0.053 mmol, 0.03 equiv.) in 10 ml of THF was added under anArgon atmosphere copper (I) iodide (10.0 mg, 0.053 mmol, 0.03 equiv.).The suspension was warmed to 60° C. overnight, taken up in 5 ml of ethylacetate and adsorbed on 4 g of silica. Purification by flashchromatography on silicagel using a 2:1 ethyl acetate/heptane mixtureyielded the title compound as a light brown solid (107 mg, 23% yield).The material was directly used in the next step without furthercharacterization.

Step 2: 2-Methyl-4-(5-phenylethynyl-pyrazin-2-ylamino)-butan-2-ol

A solution of 2-bromo-5-(phenylethynyl)pyrazine (Example 168, step 1)(158 mg, 0.061 mmol) and 4-amino-2-methylbutan-2-ol hydrochloride (255mg, 1.83 mmol, 30 equiv.) and triethylamine (185 mg, 255 ul, 1.83 mmol,30 equiv.) in 3 ml pyridine was stirred overnight at 85° C. The reactionmixture was concentrated in vaccuo. After workup withdichloromethane/water/brine, and drying over magnesium sulfate, theorganic phases were concentrated in vacuo. The crude product waschromatographed over a prepacked 20 g silica column eluting with a 25%to 100% ethyl acetate in heptane gradient which yielded the titlecompound (87.5 mg, 51% yield) as an off-white solid, MS: m/e=282.2(M+H⁺).

Step 3:6,6-Dimethyl-3-(5-(phenylethynyl)pyrazin-2-yl)-1,3-oxazinan-2-one

A solution of 2-methyl-4-(5-(phenylethynyl)pyrazin-2-ylamino)butan-2-ol(Example 168, step 2) (84 mg, 0.30 mmol) and triethylamine (91 mg, 125μl, 0.90 mmol, 3 equiv.) in 2 ml of THF was cooled to 0-5° C. andtriphosgene (89 mg, 0.30 mmol, 1 equiv.) was added in portions. Themixture was stirred for 1 hr at 0-5° C. and for 2 hours at roomtemperature. The reaction mixture was quenched with saturated sodiumcarbonate solution followed by workup with ethyl acetate/water. Theorganic layers were combined, dried and concentrated. The crude productwas chromatographed over a prepacked 20 g Silica column eluting with aheptane to 50% ethyl acetate in heptane gradient to yield the titlecompound (66.1 mg, 72% yield) as an off-white solid, MS: m/e=308.3(M+H⁺).

Example 169(RS)-3-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-5-methoxy-6,6-dimethyl-[1,3]oxazinan-2-one

Step 1:(RS)-5-Methoxy-6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a light brown solid, MS: m/e=333.2(M+H⁺), using chemistry similar to that described in Example 37, step 2from 2-bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) and(RS)-5-methoxy-6,6-dimethyl-[1,3]oxazinan-2-one (Example 114, step 2).

Step 2:(RS)-3-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-5-methoxy-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a yellow oil, MS: m/e=355.0 (M+H⁺),using chemistry similar to that described in Example 37, step 3 from(RS)-5-methoxy-6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one(Example 169, step 1) and 1-fluoro-3-iodobenzene.

Example 170(3aRS,6aSR)-1-Methyl-3-(6-phenylethynyl-pyridazin-3-yl)-hexahydro-cyclopentaimidazol-2-one

To a solution of (3aRS,6aSR)-1-methyl-hexahydro-cyclopentaimidazol-2-one(Example 106, step 3) (55 mg, 0.39 mmol, 1.5 equiv.) in 3 ml of DMF wasadded 60% sodium hydride suspension in mineral oil (17 mg, 0.42 mmol,1.6 equiv.). The white suspension was stirred for 30 min. at roomtemperature. Then 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5)(56 mg, 0.261 mmol) was added and the reaction was stirred for 1 hour atroom temperature. After workup with ethyl acetate/water, drying overmagnesium sulfate and concentration in vaccuo, the residue was purifiedby flash chromatography over silica gel eluting with a heptane to 50%ethyl acetate/heptane gradient to yield 40 mg (48% yield) of the titlecompound as an off-white solid, MS: m/e=319.1 (M+H⁺).

Example 171(RS)-6-Methyl-4-(5-phenylethynyl-pyridin-2-yl)-morpholin-3-one

Step 1: (RS)-4-(5-Iodo-pyridin-2-yl)-6-methyl-morpholin-3-one

The title compound was obtained as a white solid, MS: m/e=319.0 (M+H⁺),using chemistry similar to that described in Example 37, step 2 from2,5-diiodopyridine and (RS)-6-methyl-morpholin-3-one (CAS 127958-63-8).

Step 2: (RS)-6-Methyl-4-(5-phenylethynyl-pyridin-2-yl)-morpholin-3-one

The title compound was obtained as a light yellow solid, MS: m/e=293.1(M+H⁺), using chemistry similar to that described in Example 1, step 3from (RS)-4-(5-iodo-pyridin-2-yl)-6-methyl-morpholin-3-one (Example 171,step 1) with phenylacetylene.

Example 1726,6-Dimethyl-4-(5-phenylethynyl-pyridin-2-yl)-morpholin-3-one

Step 1: (2-Dibenzylamino-1,1-dimethyl-ethoxy)-acetic acid ethyl ester

(4.9 g, 18.2 mmol) 1-(Dibenzylamino)-2-methylpropan-2-ol (CAS344868-41-3) was dissolved in dichloroethane (50 ml) and ethyl2-diazoacetate (2.83 ml, 27.3 mmol, 1.5 equiv.) and rhodium(II) acetatedimer (200 mg, 0.455 mmol, 0.025 equiv.) were added carefully at roomtemperature. The mixture was stirred for 3 hours at 80° C. The reactionmixture was evaporated with isolute and the crude product was purifiedby flash chromatography by directly loading the residue onto a silicagel column and eluting with a heptane:ethyl acetate gradient 100:0 to70:30. The desired (2-dibenzylamino-1,1-dimethyl-ethoxy)-acetic acidethyl ester (1.03 g, 80% purity, 13% yield) was obtained as a colorlessliquid, MS: m/e=356.3 (M+H⁺).

Step 2: 6,6-Dimethyl-morpholin-3-one

(2-Dibenzylamino-1,1-dimethyl-ethoxy)-acetic acid ethyl ester (Example172, step 1) was hydrogenated in EtOH with Pd(OH)₂ for 16 hours at 60°C. The desired 6,6-dimethyl-morpholin-3-one (585 mg, 60% purity, quant.)was obtained as a colorless liquid, MS: m/e=129 (M+H⁺) and used in thenext step without further purification.

Step 3:6,6-Dimethyl-4-(5-trimethylsilanylethynyl-pyridin-2-yl)-morpholin-3-one

The title compound was obtained as a yellow oil, MS: m/e=303.2 (M+H⁺),using chemistry similar to that described in Example 37, step 2 from2-bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) and6,6-dimethyl-morpholin-3-one (Example 172, step 2).

Step 4: 6,6-Dimethyl-4-(5-phenylethynyl-pyridin-2-yl)-morpholin-3-one

The title compound was obtained as a white solid, MS: m/e=307.3 (M+H⁺),using chemistry similar to that described in Example 37, step 3 from6,6-dimethyl-4-(5-trimethylsilanylethynyl-pyridin-2-yl)-morpholin-3-one(Example 172, step 3) and iodobenzene.

Example 1731,1-Dioxo-4-(5-phenylethynyl-pyridin-2-yl)-thiomorpholin-3-one

Step 1: 4-(5-Bromo-pyridin-2-yl)-thiomorpholin-3-one

The title compound was obtained as a yellow solid, MS: m/e=273.0/274.9(M+H⁺), using chemistry similar to that described in Example 37, step 2from 2,5-dibromopyridine and thiomorpholin-3-one.

Step 2: 4-(5-Bromo-pyridin-2-yl)-1,1-dioxo-thiomorpholin-3-one

(240 mg, 0.88 mmol) 4-(5-Bromo-pyridin-2-yl)-thiomorpholin-3-one(Example 173, step 1) was dissolved in dichloroethane (10 ml) and mCPBA(300 mg, 1.76 mmol, 2 equiv.) was added at 0-5° C. The mixture wasstirred for 2 hours at 20-25° C. The reaction mixture was extracted withsaturated NaHCO₃ solution and five times dichloromethane. The organiclayers were combined, dried over Na₂SO₄ and evaporated to dryness. Thedesired 4-(5-bromo-pyridin-2-yl)-1,1-dioxo-thiomorpholin-3-one (167 mg,62% yield) was obtained as a light brown solid, MS: m/e=305.1/307.1(M+H⁺).

Step 3: 1,1-Dioxo-4-(5-phenylethynyl-pyridin-2-yl)-thiomorpholin-3-one

The title compound was obtained as a light brown solid, MS: m/e=327.2(M+H⁺), using chemistry similar to that described in Example 1, step 3from 4-(5-bromo-pyridin-2-yl)-1,1-dioxo-thiomorpholin-3-one (Example173, step 2) and phenylacetylene.

Example 174(3aSR,6aRS)-1-[6-(3-Fluoro-phenylethynyl)-pyridazin-3-yl]-3-methyl-hexahydro-cyclopentaimidazol-2-one

Step 1: 3-Chloro-6-(3-fluoro-phenylethynyl)-pyridazine

To a well stirred solution of 2-chloro-5-iodopyrazine (600 mg, 2.5mmol), 3-fluorophenyl-acetylene (315 mg, 303 μl, 2.62 mmol, 1.05 equiv.)in 7 ml of THF were added under argon atmospherebis(triphenylphosphine)-palladium(II)dichloride (175 mg, 0.250 mmol,0.02 equiv.), copper(I) iodide (23.8 mg, 0.125 mmol, 0.01 equiv.) andtriethylamine (556 mg, 761 ul, 5.49 mmol, 2.2 equiv.). The mixture wasstirred for 2 hours at room temperature. The crude mixture was filtered,adsorbed on silicagel and purified by flash chromatography over a 50 gsilicagel column using a heptane to 25% ethyl acetate in heptanegradient. The title compound (450 mg, 78% yield) was obtained as acrystalline light-yellow solid, MS: m/e=233.1, 235.0 (M+H⁺).

Step 2:(3aSR,6aRS)-1-[6-(3-Fluoro-phenylethynyl)-pyridazin-3-yl]-3-methyl-hexahydro-cyclopentaimidazol-2-one

The title compound, an off-white solid, MS: m/e=337.2 (M+H⁺), wasprepared in accordance with the general method of Example 170; startingfrom 3-chloro-6-((3-fluorophenyl)-ethynyl)pyridazine and (3aRS,6aSR)-1-methyl-hexahydro-cyclopentaimidazol-2-one.

1. A compound of formula I-A1

wherein U is ═N— or ═C(R⁵)—; V is —CH═ or —N═; W is ═CH— or ═N—; withthe proviso that no more than one of U, V or W is nitrogen. R⁵ ishydrogen, methyl or halogen; R¹ is phenyl or heteroaryl, each of whichis optionally substituted by one or two substituents, selected fromhalogen, lower alkyl and lower alkoxy; R² and R^(2′) are eachindependently hydrogen, lower alkyl, hydroxy, lower alkoxy,C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together with the carbon atomto which they are attached form a C₃-C₆-cycloalkyl group or a ringcontaining —CH₂OCH₂—; and R³ and R^(3′) are each independently hydrogen,lower alkyl, or CH₂-lower alkoxy or together with the carbon atom towhich they are attached form a C₃-C₆-cycloalkyl group; or R³ and R²together with the carbon atom to which they are attached form aC₃₋₆-cycloalkyl group or a ring containing —(CH₂)₂OCH₂—; or apharmaceutically acceptable acid addition salt, a racemic mixture, anenantiomer, an optical isomer and/or stereoisomer thereof.
 2. Thecompound of claim 1, selected from the group consisting of3-(3-fluoro-5-phenylethynyl-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one;(5RS)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;(5R or5S)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;(5S or5R)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;5,5-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;3-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one;5,5-dimethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-oxazolidin-2-one;(5RS)-5-tert-butyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;6-(5-phenylethynyl-pyridin-2-yl)-4-oxa-6-aza-spiro[2.4]heptan-5-one; and7-(5-phenylethynyl-pyridin-2-yl)-5-oxa-7-aza-spiro[3.4]octan-6-one. 3.The compound of claim 1, selected from the group consisting of3-(5-phenylethynyl-pyridin-2-yl)-1-oxa-3-aza-spiro[4.4]nonan-2-one;3-(5-phenylethynyl-pyridin-2-yl)-1-oxa-3-aza-spiro[4.5]decan-2-one;(5RS)-5-tert-butyl-5-methyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;(3aRS,6aSR)-3-(5-phenylethynyl-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one;(3aRS,6aSR)-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one;(3aRS,6aSR)-3-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-hexahydro-cyclopentaoxazol-2-one;(RS)-4,5,5-trimethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;4,4,5,5-tetramethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one;3-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one;and5,5-dimethyl-3-(5-pyrimidin-5-ylethynyl-pyridin-2-yl)-oxazolidin-2-one.4. The compound of claim 1, selected from the group consisting of5,5-dimethyl-3-[5-(1-methyl-1H-pyrazol-4-ylethynyl)-pyridin-2-yl]-oxazolidin-2-one;3-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one;3-[5-(3,4-difluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one;3-[5-(2,5-difluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one;3-[5-(6-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one;6-(5-pyridin-3-ylethynyl-pyridin-2-yl)-4-oxa-6-aza-spiro[2.4]heptan-5-one;(6SR,7RS)-3-(5-phenylethynyl-pyridin-2-yl)-hexahydro-benzooxazol-2-one;(3aSR,7aRS)-(3aRS,7RS)-1-(5-phenylethynyl-pyridin-2-yl)-hexahydro-pyrano[4,3-d]oxazol-2-one;and 5,5-dimethyl-3-(6-(phenylethynyl)pyridazin-3-yl)oxazolidin-2-one. 5.The compound of claim 1, which is(5RS)-5-tert-Butyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one. 6.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula I-A1

wherein U is ═N— or ═C(R⁵)—; V is —CH═ or —N═; W is ═CH— or ═N—; withthe proviso that only one of U, V or W is nitrogen. R⁵ is hydrogen,methyl or halogen; R¹ is phenyl or heteroaryl, each of which isoptionally substituted by one or two substituents, selected fromhalogen, lower alkyl and lower alkoxy; R² and R^(2′) are eachindependently hydrogen, lower alkyl, hydroxy, lower alkoxy,C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together with the carbon atomto which they are attached form a C₃-C₆-cycloalkyl group or a ringcontaining —CH₂OCH₂—; and R³ and R^(3′) are each independently hydrogen,lower alkyl, or CH₂-lower alkoxy or together with the carbon atom towhich they are attached form a C₃-C₆-cycloalkyl group; or R³ and R²together with the carbon atom to which they are attached form aC₃₋₆-cycloalkyl group or a ring containing —(CH₂)₂OCH₂—; or apharmaceutically acceptable acid addition salt, a racemic mixture, anenantiomer, an optical isomer and/or stereoisomer thereof and apharmaceutically acceptable carrier.